Type III Interferons, Viral Loads, Age, and Disease Severity in Young Children With Respiratory Syncytial Virus Infection.

BACKGROUND: The interplay among respiratory syncytial virus (RSV) loads, mucosal interferons (IFN), and disease severity in RSV-infected children is poorly understood. METHODS: Children <2 years of age with mild (outpatients) or severe (inpatients) RSV infection and healthy controls were enrolled, and nasopharyngeal samples obtained for RSV loads and innate cytokines quantification. Patients were stratified by age (0-6 and >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.

Nasopharyngeal Codetection of Haemophilus influenzae and Streptococcus pneumoniae Shapes Respiratory Syncytial Virus Disease Outcomes in Children.

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 <2 years old with mild (outpatients, n=115) or severe (inpatients, n=566) RSV infection, and matched healthy controls (n=161) were enrolled. Nasopharyngeal samples were obtained for RSV, Streptococcus pneumoniae, Staphylococcus aureus, Moraxella catarrhalis, and Haemophilus influenzae detection and quantitation by PCR. Multivariable models were constructed to identify variables predictive of severe disease. 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<.001). Detection of S. pneumoniae and/or H. influenzae was associated with fever, more frequent antibiotic treatment, worse radiologic findings, and higher neutrophil counts (P<.01). In adjusted analyses, S. pneumoniae/H. influenzae codetection was independentlyassociated with greater odds of hospitalization, higher disease severity scores, need for supplemental oxygen, and longer hospitalization. CONCLUSIONS: Nasopharyngeal codetection of S. pneumoniae and H. influenzae in infants with RSV infection is associated with increased disease severity.

Viral Load Dynamics and Clinical Disease Severity in Infants With Respiratory Syncytial Virus Infection.

BACKGROUND: The association between respiratory syncytial virus (RSV) loads and clinical outcomes in children remains to be defined. In most studies, viral loads (VL) were evaluated in hospitalized children and at a single time-point. We investigated the relationship between VLs and disease severity in both outpatients and inpatients with RSV infection. METHODS: We enrolled previously healthy children with RSV infection. Disease severity was defined by level of care (outpatients vs ward vs pediatric intensive care unit [PICU]), and a clinical disease severity score (CDSS). Nasopharyngeal VLs by polymerase chain reaction and CDSS were measured at enrollment and daily in inpatients. VL decay according to disease severity was analyzed using linear mixed modeling. RESULTS: From February 2015 to March 2017, we enrolled 150 infants: 39 outpatients and 111 inpatients. VLs were higher in outpatients than in age-matched inpatients. Among inpatients, initial VLs were comparable in ward and PICU patients, and preceded the peak CDSS. However, after excluding infants treated with steroids, those hospitalized in the ward had higher VLs than infants requiring PICU care (P < .001). Dynamic analyses showed that VL decay was delayed in PICU patients, especially in those treated with steroids. CONCLUSIONS: Higher VLs at presentation and a faster and consistent VL decline were both associated with less severe RSV disease in children. SUMMARY: Infants with less severe respiratory syncytial virus (RSV) disease had higher viral loads (VL) at presentation, and faster and consistent VL decline. Conversely, VL decay and overall viral exposure were prolonged and higher in infants severe RSV disease receiving steroids.

Impact of the Updated Guidance for Palivizumab Prophylaxis against Respiratory Syncytial Virus Infection: A Single Center Experience.

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 <12 months of age hospitalized with RSV infection were identified by the International Classification of Diseases, Ninth Revision codes and virology reports. Clinical, outcome data, palivizumab eligibility, and hospital charges were compared among infants 29-34 wGA in S1 vs S2. RESULTS: Of 1063 RSV hospitalizations in infants <12 months old, 7.1% (34/482) in S1 and 9.8% (57/581) in S2 occurred in 290/7-346/7 wGA infants. On the other hand, 29-34 wGA infants who were <6 months old constituted 3.5% (17/482) of RSV hospitalizations in S1 vs 7.1% (41/581) in S2 (P = .01). Among 290/7-346/7 wGA healthy infants who were <3 months old, oxygen administration (40.0% vs 78.9%; P = .05), pediatric intensive care unit admission (30.0% vs 68.4%; P = .04), mechanical ventilation (10.0% vs 52.6%; P = .04), duration of hospitalization (1.8 vs 8.8 days; P = .04), and hospital charges ($19 686 vs $30 662; P = .03) significantly increased in S2 vs S1. No differences in morbidity were observed in premature infants who were 3 to <6 and 6 to <12 months between seasons. Palivizumab eligibility decreased from 32.3% in S1 to 1.8% in S2 (P < .001). One infant died in each season. CONCLUSIONS: In the year following implementation of the 2014 palivizumab prophylaxis guidance, there was an increase in RSV hospitalizations and associated morbidity among 29-34 wGA infants of younger chronological age.

Primary succession of Bifidobacteria drives pathogen resistance in neonatal microbiota assembly.

Human microbiota assembly commences at birth, seeded by both maternal and environmental microorganisms. Ecological theory postulates that primary colonizers dictate microbial community assembly outcomes, yet such microbial priority effects in the human gut remain underexplored. Here using longitudinal faecal metagenomics, we characterized neonatal microbiota assembly for a cohort of 1,288 neonates from the UK. We show that the pioneering neonatal gut microbiota can be stratified into one of three distinct community states, each dominated by a single microbial species and influenced by clinical and host factors, such as maternal age, ethnicity and parity. A community state dominated by Enterococcus faecalis displayed stochastic microbiota assembly with persistent high pathogen loads into infancy. In contrast, community states dominated by Bifidobacterium, specifically B. longum and particularly B. breve, exhibited a stable assembly trajectory and long-term pathogen colonization resistance, probably due to strain-specific functional adaptions to a breast milk-rich neonatal diet. Consistent with our human cohort observation, B. breve demonstrated priority effects and conferred pathogen colonization resistance in a germ-free mouse model. Our findings solidify the crucial role of Bifidobacteria as primary colonizers in shaping the microbiota assembly and functions in early life.

Age-dependent Interactions Among Clinical Characteristics, Viral Loads and Disease Severity in Young Children With Respiratory Syncytial Virus Infection.

BACKGROUND: Age-dependent differences in clinical presentation and viral loads in infants and young children with respiratory syncytial virus (RSV) infection, and their correlation with disease severity are poorly defined. METHODS: Previously healthy children <2 years old with mild (outpatients) and severe (inpatients) RSV infection were enrolled and viral loads measured by polymerase chain reaction in nasopharyngeal swabs. Patients were stratified by age in 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 to 2018, we enrolled 534 children with RSV infection, 130 outpatients with mild RSV infection and 404 inpatients with severe RSV disease. Median duration of illness was 4 days for both groups, yet viral loads were higher in outpatients than in inpatients (P < 0.001). In bivariate analyses, wheezing was more frequent in outpatients of older age (>3 months) than in inpatients (P < 0.01), while fever was more common in inpatients than outpatients (P < 0.01) and its frequency increased with age. 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. CONCLUSIONS: 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.

Immune profiles provide insights into respiratory syncytial virus disease severity in young children.

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 <2 years of age. Children with mild disease (outpatients) showed higher RSV loads, greater induction of interferon (IFN) and plasma cell genes, and decreased expression of inflammation and neutrophil genes versus children with severe disease (inpatients). Additionally, only infants with severe disease had increased numbers of HLA-DRlow monocytes, not present in outpatients. Multivariable analyses confirmed that IFN overexpression was associated with decreased odds of hospitalization, whereas increased numbers of HLA-DRlow monocytes were associated with increased risk of hospitalization. These findings suggest that robust innate immune responses are associated with mild RSV infection in infants.

Trends in Age and Disease Severity in Children Hospitalized With RSV Infection Before and During the COVID-19 Pandemic.

This cohort study evaluates respiratory syncytial virus (RSV)­related hospitalizations and disease severity from 2012 to 2023 in children younger than 5 years.

Viral Bacterial Interactions in Children: Impact on Clinical Outcomes.

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.

Discharge Criteria for Bronchiolitis: An Unmet Need.

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 protocol for children <2 years of age hospitalized with bronchiolitis in a tertiary care pediatric hospital. METHODS: 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. RESULTS: 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]; P < 0.001) 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%). CONCLUSIONS: 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.

Impact on Patient Care of a Multidisciplinary Center Specializing in Colorectal and Pelvic Reconstruction.

Aim of the study: Many patients with an anorectal malformation (ARM) or pelvic anomaly have associated urologic or gynecologic problems. We hypothesized that our multidisciplinary center, which integrates pediatric colorectal, urologic, gynecologic and GI motility services, could impact a patient's anesthetic exposures and hospital visits. Methods: We tabulated during 2015 anesthetic/surgical events, endotracheal intubations, and clinic/hospital visits for all patients having a combined procedure. Main results: Eighty two patients underwent 132 combined procedures (Table 1). The median age at intervention was 3 years [0.2-17], and length of follow up was 25 months [7-31]. The number of procedures in patients who underwent combined surgery was lower as compared to if they had been done independently [1(1-5) vs. 3(2-7) (p < 0.001)]. Intubations were also lower [1[1-3] vs. 2[1-6]; p < 0.001]. Hospital length of stay was significantly lower for the combined procedures vs. the theoretical individual procedures [8 days [3-20] vs. 10 days [4-16]] p < 0.05. Post-operative clinic visits were fewer when combined visits were coordinated as compared to the theoretical individual clinic visits (urology, gynecology, and colorectal) [1[1-4] vs. 2[1-6]; p = < 0.001]. Conclusions: Patients with anorectal and pelvic malformations are likely to have many medical or surgical interventions during their lifetime. A multidisciplinary approach can reduce surgical interventions, anesthetic procedures, endotracheal intubations, and hospital/outpatient visits.

Development and clinical applications of novel antibodies for prevention and treatment of respiratory syncytial virus infection.

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.