Clinical Phenotype of Respiratory Syncytial Virus Bronchiolitis before and during the Coronavirus Disease 2019 Pandemic.

OBJECTIVE: The main objective of this report was to comprehensively analyze the clinical characteristics of children hospitalized with respiratory syncytial virus (RSV) infections in 2021 during the coronavirus disease 2019 (COVID-19) pandemic and to compare them with those in the five previous RSV seasons. We hypothesized that the clinical and demographic features of children hospitalized with RSV infection in 2021 were different from those hospitalized in previous respiratory seasons. STUDY DESIGN: In this retrospective observational study, children younger than 2 years hospitalized with RSV bronchiolitis from January 1, 2015, to December 31, 2021, at the Department of Pediatrics of the Hospital Gregorio Marañón, Madrid, Spain, were included. We compared the clinical characteristics of children hospitalized with RSV bronchiolitis in the five seasons before the COVID-19 pandemic and during the subsequent off-seasonal surge of RSV infections. RESULTS: We found a significant reduction in hospitalizations for RSV bronchiolitis during the usual winter epidemic period due to the COVID-19 pandemic. Children hospitalized with RSV infection in 2021, during the COVID-19 pandemic, were older than children hospitalized in the prepandemic period (2015-2020; 4.0 [1.6-9.2] vs. 3 [1.5-6.5] months; p < 0.01). We also found shorter duration of oxygen days during the COVID-19 period compared with previous respiratory seasons (3 [2-5] vs. 4 [2-6] days; p = 0.02). CONCLUSION: The COVID-19 pandemic modified the RSV seasonality with a significant reduction in RSV hospitalizations during the expected 2020-2021 season and a reappearance of RSV 7 months later than expected. We also found changes in the median age of children with RSV bronchiolitis during the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic compared with the prepandemic RSV seasons and shorter duration of oxygen days suggesting a modest reduction in disease severity. We hypothesize that this observation reflects the lack of RSV circulation in the previous months (April 2020-March 2021), with a larger pool of vulnerable infants that had not been previously infected. KEY POINTS: · The COVID-19 pandemic shifted RSV seasonality.. · RSV children hospitalized during the pandemic were older.. · Modest reduction in disease severity was observed during the pandemic..

Longitudinal plasma cytokine concentrations and recurrent wheezing after RSV bronchiolitis.

BACKGROUND: Respiratory syncytial virus (RSV) bronchiolitis in young children has been associated with increased risk for developing recurrent wheezing, but the underlying mechanisms, are not completely defined. We hypothesized that RSV induces a disregulated immune response defined by a distinct cytokine profile in infants at increased risk for developing recurrent wheezing. METHODS: Previously healthy infants less than 12 months of age hospitalized with a first episode of RSV bronchiolitis were enrolled and blood samples and clinical and epidemiological data collected. A group of healthy non-infected controls were enrolled in parallel. Children were followed longitudinally and subsequent blood samples collected in RSV-infected infants at one month and at one year after hospital discharge to measure longitudinal plasma concentrations of IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-17 and IL1-ß. Risk of post-RSV wheezing was assessed by Poisson modelling. RESULTS: From October 2008 to March 2012 we enrolled 37 infants hospitalized with RSV bronchiolitis and 9 healthy age-matched controls. Within the RSV cohort, 17 (46%) children developed recurrent wheezing within the following 12 months. Plasma cytokine profiles measured during the acute infection were similar in children who developed recurrent wheezing versus those who did not, but lower in healthy controls vs RSV infants who subsequently developed wheezing. At one month and 12 months post-acute RSV infection, infants who developed recurrent wheezing had higher IFN-γ plasma concentrations versus those with no-wheezing (p < 0.05). Moreover, IFN-γ concentrations were identified as independent predictor of post-RSV wheezing. CONCLUSIONS: Children with RSV-associated recurrent wheezing had persistently elevated plasma concentrations of IFN-γ for a year after acute infection, suggesting that this cytokine could be used as a biomarker for risk of recurrent wheezing and possibly plays a role in the pathogenesis of this condition.

The clinical relevance of the microbiome when managing paediatric infectious diseases-Narrative review.

In recent years, the field of infectious diseases has been hit by the overwhelming amount of information generated while the human microbiome is being disentangled. Based on the interaction between the microbiota and the immune system, the implications regarding infectious diseases are probably major and remain a challenge. AIMS: This review was conceived as a comprehensive tool to provide an overview of the available evidence regarding the influence of the microbiome on infectious diseases in children. METHODS: We present the main findings aroused from microbiome research in prevention, diagnosis and treatment of infectious disease under a paediatric perspective, to inform clinicians of the potential relevance of microbiome-related knowledge for translation to clinical practice. RESULTS AND CONCLUSION: The evidence shown in this review highlights the numerous research gaps ahead and supports the need to move forward to integrating the so-called microbiome thinking into our routine clinical practice.

The journey to a respiratory syncytial virus vaccine.

OBJECTIVE: The high burden associated with respiratory syncytial virus (RSV) has made the development of RSV vaccine(s) a global health high priority. This review summarizes the journey to an RSV vaccine, the different strategies and challenges associated with the development of preventive strategies for RSV, and the diverse products that are undergoing clinical testing. DATA SOURCES: Studies on RSV biology, immunology, epidemiology, and monoclonal antibodies (mAbs) and vaccines were searched using MEDLINE. We also searched PATH.org and ClinicalTrials.gov for updated information regarding the status of RSV vaccines and mAbs undergoing clinical trials. STUDY SELECTIONS: We selected relevant studies conducted in infants and young children, pregnant women, and elderly population for the prevention of RSV infection. RESULTS: Identification of a safe and immunogenic vaccine has been an important but elusive initiative for more than 60 years for different reasons, including the legacy of formalin-inactivated vaccine, our limited understanding of the immune response to RSV and how it relates to clinical disease severity, or the need for different end points according to the different vaccine platforms. Nevertheless, there are currently 39 vaccines and mAbs under development and 19 undergoing clinical trials. CONCLUSION: Over the past decade, there have been significant advances in our knowledge of RSV molecular and structural biology and in understanding the human immune response to RSV. Despite the barriers, there are several promising mAbs and RSV vaccines undergoing clinical trials that hope to offer protection to the most vulnerable populations.

Expert consensus on palivizumab use for respiratory syncytial virus in developed countries.

Respiratory syncytial virus (RSV) infection is a leading cause of hospitalisation in early childhood and palivizumab is the only licensed intervention for prevention. Palivizumab guidelines should reflect the latest evidence, in addition to cost-effectiveness and healthcare budgetary considerations. RSV experts from Europe, Canada and Israel undertook a systematic review of the evidence over the last 5 years and developed recommendations regarding prophylaxis in industrialised countries. Almost 400 publications were reviewed. This group recommended palivizumab for: preterm infants (<29 and ≤31 weeks gestational age [wGA] and ≤9 and ≤6 months of age, respectively; high-risk 32-35wGA), former preterm children ≤24 months with chronic lung disease/bronchopulmonary dysplasia, children ≤24 months with significant congenital heart disease; and other high-risk populations, such as children ≤24 months with Down syndrome, pulmonary/neuromuscular disorders, immunocompromised, and cystic fibrosis. Up to 5 monthly doses should be administered over the RSV season. It is our impression that the adoption of these guidelines would help reduce the burden of RSV.

Interaction between healthcare professionals and parents is a key determinant of parental distress during childhood hospitalisation for respiratory syncytial virus infection (European RSV Outcomes Study [EROS]).

AIM: We characterised the distress that parents experienced when their child was hospitalised for respiratory syncytial virus (RSV) infection. METHODS: This survey-based, observational study was conducted during 2014-2015. Meetings were held in Spain and Italy, with 24 parents of RSV hospitalised infants and 11 healthcare professionals experienced in RSV, which identified 110 factors related to parental distress. The resulting questionnaire was completed by another 105 Spanish and Italian parents and 56 healthcare professionals, to assess the impact these factors had on parental distress, using a scale from 0 to 10 (very unimportant to very important). RESULTS: The five most important factors for parents were: healthcare professionals' awareness of the latest developments, readmission, reinfections, painful procedures and positive experiences with healthcare professionals. Healthcare professionals associated only medical factors with a meaningful impact on parents. Half of the six medical factors were given similar importance by both groups and the overall scoring for the 110 factors was comparable, with a correlation coefficient of 0.80. A primary concern on discharge was ongoing support. CONCLUSION: The relationship between parents and healthcare professionals was a significant factor in determining parental distress. Healthcare professionals appeared to have a good understanding of the overall impact on parents, particularly the key medical factors.

Respiratory Syncytial Virus Genotypes, Host Immune Profiles, and Disease Severity in Young Children Hospitalized With Bronchiolitis.

Background: Data on how respiratory syncytial virus (RSV) genotypes influence disease severity and host immune responses is limited. Here, we characterized the genetic variability of RSV during 5 seasons, and evaluated the role of RSV subtypes, genotypes, and viral loads in disease severity and host transcriptional profiles. Methods: A prospective, observational study was carried out, including a convenience sample of healthy infants hospitalized with RSV bronchiolitis. Nasopharyngeal samples for viral load quantitation, typing, and genotyping, and blood samples for transcriptome analyses were obtained within 24 hours of hospitalization. Multivariate models were constructed to identify virologic and clinical variables predictive of clinical outcomes. Results: We enrolled 253 infants (median age 2.1 [25%-75% interquartile range] months). RSV A infections predominated over RSV B and showed greater genotype variability. RSV A/GA2, A/GA5, and RSV B/BA were the most common genotypes identified. Compared to GA2 or BA, infants with GA5 infections had higher viral loads. GA5 infections were associated with longer hospital stay, and with less activation of interferon and increased overexpression of neutrophil genes. Conclusions: RSV A infections were more frequent than RSV B, and displayed greater variability. GA5 infections were associated with enhanced disease severity and distinct host immune responses.

Conservation of G-Protein Epitopes in Respiratory Syncytial Virus (Group A) Despite Broad Genetic Diversity: Is Antibody Selection Involved in Virus Evolution?

UNLABELLED: Worldwide G-glycoprotein phylogeny of human respiratory syncytial virus (hRSV) group A sequences revealed diversification in major clades and genotypes over more than 50 years of recorded history. Multiple genotypes cocirculated during prolonged periods of time, but recent dominance of the GA2 genotype was noticed in several studies, and it is highlighted here with sequences from viruses circulating recently in Spain and Panama. Reactivity of group A viruses with monoclonal antibodies (MAbs) that recognize strain-variable epitopes of the G glycoprotein failed to correlate genotype diversification with antibody reactivity. Additionally, no clear correlation was found between changes in strain-variable epitopes and predicted sites of positive selection, despite both traits being associated with the C-terminal third of the G glycoprotein. Hence, our data do not lend support to the proposed antibody-driven selection of variants as a major determinant of hRSV evolution. Other alternative mechanisms are considered to account for the high degree of hRSV G-protein variability. IMPORTANCE: An unusual characteristic of the G glycoprotein of human respiratory syncytial virus (hRSV) is the accumulation of nonsynonymous (N) changes at higher rates than synonymous (S) changes, reaching dN/dS values at certain sites predictive of positive selection. Since these sites cluster preferentially in the C-terminal third of the G protein, like certain epitopes recognized by murine antibodies, it was proposed that immune (antibody) selection might be driving the apparent positive selection, analogous to the antigenic drift observed in the influenza virus hemagglutinin (HA). However, careful antigenic and genetic comparison of the G glycoprotein does not provide evidence of antigenic drift in the G molecule, in agreement with recently published data which did not indicate antigenic drift in the G protein with human sera. Alternative explanations to the immune-driven selection hypothesis are offered to account for the high level of G-protein genetic diversity highlighted in this study.