Severe Respiratory Syncytial Virus Research Articles

Lower respiratory tract infections in early life are associated with obstructive sleep apnea diagnosis during childhood in a large birth cohort.

Several birth cohorts have defined the pivotal role of early lower respiratory tract infections (LRTI) in the inception of pediatric respiratory conditions. However, the association between early LRTI and the development of obstructive sleep apnea (OSA) in children has not been established. To investigate whether early LRTIs increase the risk of pediatric OSA, we analyzed clinical data in children followed during the first 5 years in the Boston Birth Cohort (n = 3114). Kaplan-Meier survival estimates and Cox proportional hazards models adjusted by pertinent covariates were used to evaluate the risk of OSA by the age of 5 years between children with LRTI during the first 2 years of life in comparison to those without LRTI during this period. Early life LRTI increased the risk of pediatric OSA independently of other pertinent covariates and risk factors (hazard ratio, 1.53; 95% CI, 1.15 to 2.05). Importantly, the association between LRTI and pediatric OSA was limited to LRTIs occurring during the first 2 years of life. Complementarily to this finding, we observed that children who had severe respiratory syncytial virus bronchiolitis during infancy had two times higher odds of OSA at 5 years in comparison with children without this exposure (odds ratio, 2.09; 95% CI, 1.12 to 3.88). Children with severe LRTIs in early life have significantly increased risk of developing OSA during the first 5 years of life. Our results offer a new paradigm for investigating novel mechanisms and interventions targeting the early pathogenesis of OSA in the pediatric population.

Severe Clinical Outcomes Among Adults Hospitalized With Respiratory Syncytial Virus Infections, New York City, 2017-2019.

Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in older adults. We assessed severe clinical outcomes among hospitalized adults that were associated with RSV infections. We performed a nested retrospective study in 3 New York City hospitals during 2 respiratory viral seasons, October 2017-April 2018 and October 2018-April 2019, to determine the proportion of patients with laboratory-confirmed RSV infection who experienced severe outcomes defined as intensive care unit (ICU) admission, mechanical ventilation, and/or death. We assessed factors associated with these severe outcomes and explored the effect of RSV-associated hospitalizations on changes in the living situations of surviving patients. Of the 403 patients studied (median age, 69 years), 119 (29.5%) were aged ≥80. Severe outcomes occurred in 19.1% of patients, including ICU admissions (16.4%), mechanical ventilation (12.4%), and/or death (6.7%). Patients admitted from residential living facilities had a 4.43 times higher likelihood of severe RSV infection compared with patients who were living in the community with or without assistance from family or home health aides. At discharge, 56 (15.1%) patients required a higher level of care than at admission. RSV infection was associated with severe outcomes in adults. Living in a residential facility at admission was a risk factor for severe outcomes and could be a proxy for frailty rather than an independent risk factor. Our data support the development of prevention strategies for RSV infection in older populations, especially older adults living in residential living facilities.

The Burden of Respiratory Syncytial Virus in Children Under 2 Years of Age in a Rural Community in Maharashtra, India.

BackgroundGlobally, respiratory syncytial virus (RSV) is a common cause of acute lower tract infection (LRTI) in children younger than 2 years of age, but there are scant population-based studies on the burden of RSV illness in rural communities and no community studies in preterm infants.MethodsActive surveillance of LRTI was performed in the community and hospital setting for the population of 93 tribal villages in Melghat, Central India, over 4 respiratory seasons. A nasopharyngeal swab was obtained from cases presenting as a severe LRTI for molecular analysis of respiratory pathogens including RSVA and B.ResultsHigh rates of RSV-associated LRTI were found in preterm and term infants beyond 6 months of age, extending into the second year of life. Community severe RSV LRTI rates for 0–11 months of age was 22.4 (18.6–27.0)/1000 child-years (CY) and the hospital-associated rate was 14.1 (11.1–17.8)/1000 CY. For preterm infants, these rates were 26.2 (17.8–38.5)/1000 CY and 12.6 (7.2–22.0)/1000 CY. Comparable rates in the first 6 months were 15.9 (11.8–21.4)/1000 CY and 12.9 (9.3–18.0)/1000 CY in term infants and 26.3 (15.4–45.0)/1000 CY and 10.1 (4.2–24.2)/1000 CY for preterms. The single RSV B season had higher incidences of RSV LRTI in every age group than the 2 RSV A seasons in both preterm and term infants. There were 11 deaths, all term infants.ConclusionsStudies restricted to the healthcare settings significantly underestimate the burden of RSV LRTI and preterm and term infants have comparable burdens of disease in this rural community.

Mortality From Respiratory Syncytial Virus in Children Under 2 Years of Age: A Prospective Community Cohort Study in Rural Maharashtra, India.

BackgroundAlthough respiratory syncytial virus (RSV) is the most important viral cause of lower respiratory tract infection deaths in infants, there are few data on infant community deaths caused by RSV.MethodsThis was an active surveillance of children younger than 2 years of age in 93 villages, 5 primary health centers, and 3 hospitals serving these villages. Village health workers and counselors at the health facilities monitored all lower respiratory tract infections (LRTIs) in consented subjects. Children with severe, or very severe LRTIs and all who died, had nasopharyngeal swabs collected for detection of RSV by molecular methods.ResultsIn the 12 134 subjects, there were 2064 episodes of severe LRTIs and 1732 of very severe LRTIs, of which 271 and 195, respectively, had RSV. Fifteen of 16 (94%) children with RSV died of LRTIs, 14 in the community and 1 in the hospital. The case fatality ratios for severe RSV LRTIs in the first 6 months of life were 3/52 (7.1%) and 1/36 (2.8%) in the community and hospital, respectively. Of those with very severe LRTIs in the community, 17.6% died. There were no very severe RSV LRTI hospital deaths. The adjusted RSV LRTI mortality rates ranged from 1.0 to 3.0/1000 child-years (CY) overall, and 2.0 to 6.1/1000 CY, accounting for 20% of the LRTI deaths and 10% of the postneonatal infant mortality.ConclusionsCommunity deaths from RSV account for the majority of RSV LRTI deaths, and efforts at prevention should be preferentially directed at populations where access to care is limited.

Bringing Preventive RSV Monoclonal Antibodies to Infants in Low- and Middle-Income Countries: Challenges and Opportunities.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (LRTIs) in infants. Most deaths occur in infants under 3 months old, and those living in low and middle-income countries (LMICs). There are no maternal or infant RSV vaccines currently approved. An RSV monoclonal antibody (mAb) could fill the gap until vaccines are available. It could also be used when a vaccine is not given, or when there is insufficient time to vaccinate and generate an antibody response. The only currently approved RSV mAb, palivizumab, is too costly and needs monthly administration, which is not possible in LMICs. It is imperative that a safe, effective, and affordable mAb to prevent severe RSV LRTI be developed for infants in LMICs. Next generation, half-life extended mAbs in clinical development, such as nirsevimab, show promise in protecting infants against RSV LRTI. Given that a single dose could cover an entire 5-month season, there is an opportunity to make RSV mAbs affordable for LMICs by investing in improvements in manufacturing efficiency. The challenges of using RSV mAbs in LMICs are the complexities of integrating them into existing healthcare delivery programs and surveillance systems, both of which are needed to define seasonal patterns, and monitor for escape mutants. Collaboration with key stakeholders such as the World Health Organization and Gavi, the Vaccine Alliance, will be essential for achieving this goal.

Risk factors for hospitalisation due to respiratory syncytial virus infection in children receiving prophylactic palivizumab.

Respiratory syncytial virus (RSV) is a common pathogen that causes extremely severe respiratory symptoms in the first few weeks and months of life. In infants with cardiopulmonary diseases, RSV infections have a significant clinical impact. Palivizumab, a humanised monoclonal antibody for RSV, has been shown to significantly reduce the rate of hospitalisation of high-risk infants diagnosed with RSV. However, we have experienced a significant number of RSV infections in our institution that required hospitalisation or intensive care, despite the administration of palivizumab. This study aimed to analyse the risk factors associated with severe RSV despite the use of palivizumab. We retrospectively reviewed the medical records of 688 patients who visited or were admitted to our hospital and received palivizumab. Thirty-seven (5.4%) patients required hospitalisation for RSV, despite receiving palivizumab. In addition, 31 of these patients (83.8%) required hospitalisation out of season for palivizumab injection. Preterm birth (≤ 28-week gestation), bronchopulmonary dysplasia (BPD), and trisomy 21 were risk factors for RSV-related hospitalisation in infected patients, despite receiving palivizumab. Furthermore, subgroup analysis of 69 patients with RSV revealed that hemodynamically significant congenital heart disease (CHD) was also a risk factor for RSV-related hospitalisation.Conclusion: Preterm birth (≤ 28weeks of gestation), BPD, trisomy 21, hemodynamically significant CHD, and CHD requiring surgery or cardiac catheterisation/intervention during infancy could be considered when determining whether year-round administration of palivizumab is appropriate. What is Known: • Respiratory syncytial virus causes severe respiratory symptoms in infants, particularly those with cardiopulmonary diseases. • The use of palivizumab has reduced the rate of hospitalisation of infants diagnosed with RSV. Despite this, the rate of hospitalisation is still high. What is New: •We identified that preterm birth (≤ 28-week gestation), bronchopulmonary dysplasia, trisomy 21, andhemodynamically significant congenital heart disease were risk factors for RSV-related hospitalisation, even afterreceiving palivizumab treatment. •High-risk infants should be closely monitored and the prolonged use of palivizumab should be considered.

Adeno-Associated Virus Vector-Mediated Expression of Antirespiratory Syncytial Virus Antibody Prevents Infection in Mouse Airways

Infants and older adults are especially vulnerable to infection by respiratory syncytial virus (RSV), which can cause significant illness and irreparable damage to the lower respiratory tract and for which an effective vaccine is not readily available. Palivizumab, a recombinant monoclonal antibody (mAb), is an approved therapeutic for RSV infection for use in high-risk infants only. Due to several logistical issues, including cost of goods and scale-up limitations, palivizumab is not approved for other populations that are vulnerable to severe RSV infections, such as older adults. In this study, we demonstrate that intranasal delivery of adeno-associated virus serotype 9 (AAV9) vector expressing palivizumab or motavizumab, a second-generation version of palivizumab, significantly reduced the viral load in the lungs of the BALB/c mouse model of RSV infection. Notably, we demonstrate that AAV9 vector-mediated prophylaxis against RSV was effective despite the presence of serum-circulating neutralizing AAV9 antibodies. These findings substantiate the feasibility of repeatedly administering AAV9 vector to the airway for seasonal prophylaxis against RSV, thereby expanding the application of vectored delivery of mAbs as an effective prophylaxis strategy against various airborne viruses.

Monitoring Severity of Respiratory Syncytial Virus (RSV) in Infants and Young Children Using the Pediatric RSV Electronic Severity and Outcome Rating System (PRESORS): Results of Initial Quantitative Validation.

PurposePRESORS ClinRO completed by clinicians and ObsRO completed by caregivers were developed to characterize the clinical course of respiratory syncytial virus (RSV) infection. This study describes preliminary analysis of PRESORS’ measurement properties using clinical trial data.Patients and MethodsPRESORS ClinRO and ObsRO data were collected in a 28-day randomized, double-blind, Phase 1b trial of JNJ-53718678 or placebo in infants and children ≤24 months of age treated for RSV infection in hospitals. PRESORS data were scored and key psychometric properties of scores were evaluated, including ability to discriminate between known groups and to detect change over time. Time to resolution of RSV signs was explored using two responder definitions.ResultsDaily completion rates for PRESORS ClinRO and ObsRO were high for the 44 children in the study (median: 100% and 93%, respectively). Large floor effects were observed at baseline for signs of severe RSV infection that were either absent (cyanosis, fever, apnea) or rarely reported (reduced urination/dehydration, vomiting). Implausible ObsRO ratings suggested some caregivers could not accurately measure heart rate. Known-group validity was confirmed: children in poor health based on baseline ClinRO had mean baseline composite scores that were significantly worse for both ObsRO (p=0.001) and ClinRO (p<0.001) compared to those with better overall health. ObsRO (p=0.009) and ClinRO (p<0.001) composite scores were responsive to change in overall health status from baseline to Day 3. Mean scores for RSV sign dimensions decreased rapidly from baseline to Day 7 except for coughing and sleep ratings by caregivers. Time to recovery varied greatly depending on definitions used.ConclusionPRESORS ClinRO and ObsRO can inform endpoints and enable monitoring the clinical course of RSV in pediatric trials. Improved alignment between ClinRO and ObsRO and revisions ensuring caregivers can assess all signs will be addressed in revised PRESORS.

Respiratory Syncytial Virus (RSV)-Specific Antibodies in Pregnant Women and Subsequent Risk of RSV Hospitalization in Young Infants.

BackgroundThe fusion (F) glycoprotein of respiratory syncytial virus (RSV) represents the major neutralizing antigen, and antibodies against the pre-F conformation have the most potent neutralizing activity. This study aimed to assess the correlation between maternal antibody titers against the pre-F, post-F, and G glycoproteins and the child’s risk of developing severe RSV bronchiolitis early in infancy.MethodsWe identified previously healthy term infants <3 months of age hospitalized with RSV bronchiolitis from December 2015 to March 2016. We measured IgG antibody titers to pre-F, post-F, and G proteins in maternal sera obtained at 9–12 weeks of pregnancy of these hospitalized infants’ mothers (n = 94) and compared them with serum antibody titers of control pregnant mothers (n = 130) whose children were not hospitalized.ResultsAll maternal samples (n = 224) had detectable pre-F antibodies. Pre-F antibody titers were significantly lower in mothers whose infants were hospitalized with RSV bronchiolitis compared with those mothers whose infants were not hospitalized (23.9 [range (or antibody titer range), 1.4–273.7] µg/L vs 30.6 [XXX, 3.4–220.0] µg/L; P = .0026). There were no significant differences in maternal post-F and G antibody titers between hospitalized and nonhospitalized infants.ConclusionsOur findings indicate that maternal pre-F antibodies are fundamental for providing immune protection to the infant.

The azithromycin to prevent wheezing following severe RSV bronchiolitis-II clinical trial: Rationale, study design, methods, and characteristics of study population

Severe respiratory syncytial virus (RSV) bronchiolitis in early life is a significant risk factor for future recurrent wheeze (RW) and asthma. The goal of the Azithromycin to Prevent Wheezing following severe RSV bronchiolitis II (APW-RSV II) clinical trial is to evaluate if azithromycin treatment in infants hospitalized with RSV bronchiolitis reduces the occurrence of RW during the preschool years.The APW-RSV II clinical trial is a double-blind, placebo-controlled, parallel-group, randomized trial, including otherwise healthy participants, ages 30 days-18 months, who are hospitalized due to RSV bronchiolitis. The study includes an active randomized treatment phase with azithromycin or placebo for 2 weeks, and an observational phase of 18–48 months. Two hundred participants were enrolled during three consecutive RSV seasons beginning in the fall of 2016 and were randomized to receive oral azithromycin 10 mg/kg/day for 7 days followed by 5 mg/kg/day for an additional 7 days, or matched placebo. The study hypothesis is that in infants hospitalized with RSV bronchiolitis, the addition of azithromycin therapy to routine bronchiolitis care would reduce the likelihood of developing post-RSV recurrent wheeze (≥3 episodes). The primary clinical outcome is the occurrence of a third episode of wheezing, which is evaluated every other month by phone questionnaires and during yearly in-person visits.A secondary objective of the APW-RSV II clinical trial is to examine how azithromycin therapy changes the upper airway microbiome composition, and to determine if these changes are related to the occurrence of post-RSV RW. Microbiome composition is characterized in nasal wash samples obtained before and after the study treatments.This clinical trial may identify the first effective intervention applied during severe RSV bronchiolitis to reduce the risk of post-RSV RW and ultimately asthma.

Balancing precision versus cohort transcriptomic analysis of acute and recovery phase of viral bronchiolitis.

Viral infections affecting the lower respiratory tract place enormous burdens on hospitals. As neither vaccines nor antiviral agents exist for many viruses, understanding risk factors and outcomes in each patient using minimally invasive analysis, such as blood, can lead to improved health care delivery. A cohort of PAXgene RNA sequencing of infants admitted with moderate or severe acute bronchiolitis and respiratory syncytial virus were compared with case-control statistical analysis and cohort-based outlier mapping for precision transcriptomics. Patients with severe bronchiolitis had signatures connected to the immune system, interferon signaling, and cytokine signaling, with marked sex differences in XIST, RPS4Y1, KDM5D, and LINC00278 for severity. Several patients had unique secondary infections, cytokine activation, immune responses, biological pathways, and immune cell activation, highlighting the need for defining patient-level transcriptomic signatures. Balancing relative contributions of cohort-based biomarker discoveries with patient's biological responses is needed to understand the totality of mechanisms of adverse outcomes in viral bronchiolitis.

Respiratory syncytial virus and airway microbiota - A complex interplay and its reflection on morbidity.

The immunopathology of respiratory syncytial virus (RSV) infection varies considerably, severe disease occurring only in a minority of the affected children. The variability of the clinical presentation is in part explained by viral and environmental factors but, in infants and young children, disease severity is certainly linked to the physiologic immaturity of the innate and adaptive immune system. There is evidence that the maturation of the host immune response is positively influenced by the composition of the nasopharyngeal microbiome that, promoting an efficient reaction, can counteract the predisposition to develop viral respiratory infections and lower the risk of disease severity. However, interaction between the nasopharyngeal microbiota and respiratory viruses can be bidirectional since microbial dysbiosis may also represent a reflection of the disease-induced alterations of the local milieu. Moreover, viruses like RSV can also increase the virulence of potential pathogens in nasopharynx, a main reservoir of bacteria, and therefore promote their spread to the lower airways causing superinfection. Moreover, if negative changes in microbial community composition in early life may constitute a heightened risk toward severe RSV respiratory infection, on the contrary specific groups of microorganisms seem to be associated with protection. A better understanding into the potential negative and positive role of the different nasopharyngeal bacterial species on RSV infection may improve primary prevention and possibly care of this highly contagious disorder.

Parents of Children With Medical Complexity Are Essential Health Care Personnel

* Abbreviations: CDC — : Centers for Disease Control and Prevention CMC — : children with medical complexity COVID-19 — : coronavirus disease 2019 The coronavirus disease 2019 (COVID-19) pandemic has created a national and global crisis. The United States has invested tremendous effort and resources to fast track severe acute respiratory syndrome coronavirus 2 vaccines from conception to market in 1 year, an amazing scientific achievement. Public health experts are now leading the distribution of COVID-19 vaccines. The Centers for Disease Control and Prevention (CDC) recommends that health care personnel be offered COVID-19 vaccination during the early phases of distribution. Health care personnel are broadly defined and include emergency medical service personnel, nurses and nursing assistants, physicians, technicians, therapists, dentists, dental hygienists and assistants, phlebotomists, pharmacists, students and trainees, contractual staff, dietary and food services staff, environmental services staff, and administrative staff. We strongly recommend that parents and family caregivers (collectively referred to as parents in this article) of children with medical complexity (CMC) be included in the early phases of vaccine distribution because they serve as essential frontline health care personnel. CMC have significant chronic health conditions that involve multiple organ systems, substantial health service needs, major functional limitations, and high health resource use. They have high levels of medical fragility, technology dependencies (tracheostomies, ventilators, feeding tubes, intrathecal baclofen infusion systems, and others), and psychosocial complexities. We identify CMC as those who have ≥3 organ systems affected (≥3 Feudtner … Address correspondence to Nancy A. Murphy, MD, FAAP, FAAPMR, Division of Pediatric Physical Medicine & Rehabilitation, Department of Pediatrics, School of Medicine, University of Utah, 81 North Mario Capecchi Dr, Salt Lake City, UT 84113. E-mail: nancy.murphy{at}hsc.utah.edu

Tissue resident memory T cell responses to RSV infection are reduced in infant mice compared to adults

Abstract Tissue resident memory T cells (TRMs) are an important yet incompletely understood cell population that enhance the clearance of respiratory syncytial virus (RSV) infection in both humans and animal models of disease. Limited data in an influenza model of disease suggests the establishment of TRMs in infants is impaired, but the establishment of TRMs during infant RSV infection is unknown. The purpose of this study was to characterize the quantity and function of infant TRM responses to RSV infection. To address this, BALB/c mice were infected with RSV as 10-day old mice or as 6–8-week-old adults. Peripheral T cells were then depleted using FTY720 at the time of an RSV re-challenge 4–5 weeks later. TRM response was evaluated using flow cytometry; viral titers and histological staining were used to assess disease outcomes. Mice infected as infants had significantly lower total numbers of CD4+ and CD8+ TRMs compared to those infected as adults. Furthermore, TRMs established in infancy showed a Th2-biased response, with increased production of IL-4 and IL-10 compared to adults, while adult TRMs produced more granzyme B from CD8+ cells and increased IFNγ from both CD4+ and CD8+ T cells. Mice infected in infancy also showed increased %PAS positive airways compared to those infected initially as adults, suggesting more severe RSV disease. In conclusion, infants have reduced ability to establish TRMs following RSV infection and their TRM population exhibits Th2 skewing. Further studies are needed to elucidate the mechanisms that prevent effective establishment of TRMs following infant pulmonary infections.

Monoclonal Antibodies for Prevention of Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is the leading cause of hospitalizations in infants worldwide. Palivizumab, a humanized monoclonal antibody against the RSV F protein, is the only licensed agent for prevention of severe RSV infection in high-risk infants. Palivizumab is administered intramuscularly, every month during the RSV season, usually 5 doses are required. In recent years, the resolution of the structure of the RSV F protein, with identification of potent neutralizing epitopes, and new technologies for production of monoclonal antibodies (mAbs) have facilitated the development of new alternative strategies for the prevention of RSV infections. One promising approach is a new generation of mAbs directed to new neutralizing epitopes and with prolonged half life. These enhanced mAbs are expected to provide adequate protection during the complete RSV season with a single intramuscular (IM) dose. The long-term goal of this approach is to provide passive immunization for the prevention of RSV lower respiratory tract infection to all infants (preterm and full term) in the first months of life before their initial exposure to RSV.

Burden of respiratory syncytial virus bronchiolitis on the Dutch pediatric intensive care units

Respiratory syncytial virus (RSV) bronchiolitis causes substantial morbidity and mortality in young children, but insight into the burden of RSV bronchiolitis on pediatric intensive care units (PICUs) is limited. We aimed to determine the burden of RSV bronchiolitis on the PICUs in the Netherlands. Therefore, we identified all children ≤ 24 months of age with RSV bronchiolitis between 2003 and 2016 from a nationwide PICU registry. Subsequently we manually checked their patient records for correct diagnosis and collected patient characteristics, additional clinical data, respiratory support modes, and outcome. In total, 2161 children were admitted to the PICU for RSV bronchiolitis. The annual number of admissions increased significantly during the study period (β 4.05, SE 1.27, p = 0.01), and this increase was mostly driven by increased admissions in children up to 3 months old. Concomitantly, non-invasive respiratory support significantly increased (β 7.71, SE 0.92, p < 0.01), in particular the use of high flow nasal cannula (HFNC) (β 6.69, SE 0.96, p < 0.01), whereas the use of invasive ventilation remained stable.Conclusion: The burden of severe RSV bronchiolitis on PICUs has increased in the Netherlands. Concomitantly, the use of non-invasive respiratory support, especially HFNC, has increased.What is Known:• RSV bronchiolitis is a major cause of childhood morbidity and mortality and may require pediatric intensive care unit admission.• The field of pediatric critical care for severe bronchiolitis has changed due to increased non-invasive respiratory support options.What is New:• The burden of RSV bronchiolitis for the Dutch PICUs has increased. These data inform future strategic PICU resource planning and implementation of RSV preventive strategies.• There was a significant increase in the use of high flow nasal cannula at the PICU, but the use of invasive mechanical ventilation did not decrease.

NLRP3-Inflammasome Inhibition during Respiratory Virus Infection Abrogates Lung Immunopathology and Long-Term Airway Disease Development.

Respiratory syncytial virus (RSV) infects most infants by two years of age. It can cause severe disease leading to an increased risk of developing asthma later in life. Previously, our group has shown that RSV infection in mice and infants promotes IL-1β production. Here, we characterized the role of NLRP3-Inflammasome activation during RSV infection in adult mice and neonates. We observed that the inhibition of NLRP3 activation using the small molecule inhibitor, MCC950, or in genetically modified NLRP3 knockout (Nlrp3−/−) mice during in vivo RSV infection led to decreased lung immunopathology along with a reduced expression of the mucus-associated genes and reduced production of innate cytokines (IL-1β, IL-33 and CCL2) linked to severe RSV disease while leading to significant increases in IFN-β. NLRP3-inflammasome inhibition or deletion diminished Th2 cytokines and inflammatory cell infiltration into the lungs. Furthermore, NLRP3 inhibition or deletion during early-life RSV infection led to reducing viral-exacerbated allergic response in a mouse model of RSV-induced allergy exacerbation. Here, we demonstrated the critical role of NLRP3-inflammasome activation in RSV immunopathology and the related long-term airway alteration. Moreover, these findings suggest the NLRP3-inflammasome as a potential therapeutic target to attenuate severe RSV disease and limit childhood asthma development.

Safety, tolerability, and immunogenicity of the respiratory syncytial virus prefusion F subunit vaccine DS-Cav1: a phase 1, randomised, open-label, dose-escalation clinical trial

Multiple active vaccination approaches have proven ineffective in reducing the substantial morbidity and mortality caused by respiratory syncytial virus (RSV) in infants and older adults (aged ≥65 years). A vaccine conferring a substantial and sustainable boost in neutralising activity is required to protect against severe RSV disease. To that end, we evaluated the safety and immunogenicity of DS-Cav1, a prefusion F subunit vaccine. In this randomised, open-label, phase 1 clinical trial, the stabilised prefusion F vaccine DS-Cav1 was evaluated for dose, safety, tolerability, and immunogenicity in healthy adults aged 18-50 years at a single US site. Participants were assigned to receive escalating doses of either 50 μg, 150 μg, or 500 μg DS-Cav1 at weeks 0 and 12, and were randomly allocated in a 1:1 ratio within each dose group to receive the vaccine with or without aluminium hydroxide (AlOH) adjuvant. After 71 participants had been randomised, the protocol was amended to allow some participants to receive a single vaccination at week 0. The primary objectives evaluated the safety and tolerability at every dose within 28 days following each injection. Neutralising activity and RSV F-binding antibodies were evaluated from week 0 to week 44 as secondary and exploratory objectives. Safety was assessed in all participants who received at least one vaccine dose; secondary and exploratory immunogenicity analysis included all participants with available data at a given visit. The trial is registered with ClinicalTrials.gov, NCT03049488, and is complete and no longer recruiting. Between Feb 21, 2017, and Nov 29, 2018, 244 participants were screened for eligibility and 95 were enrolled to receive DS-Cav1 at the 50 μg (n=30, of which n=15 with AlOH), 150 μg (n=35, of which n=15 with AlOH), or 500 μg (n=30, of which n=15 with AlOH) doses. DS-Cav1 was safe and well tolerated and no serious vaccine-associated adverse events deemed related to the vaccine were identified. DS-Cav1 vaccination elicited robust neutralising activity and binding antibodies by 4 weeks after a single vaccination (p<0·0001 for F-binding and neutralising antibodies). In analyses of exploratory endpoints at week 44, pre-F-binding IgG and neutralising activity were significantly increased compared with baseline in all groups. At week 44, RSV A neutralising activity was 3·1 fold above baseline in the 50 μg group, 3·8 fold in the 150 μg group, and 4·5 fold in the 500 μg group (p<0·0001). RSV B neutralising activity was 2·8 fold above baseline in the 50 μg group, 3·4 fold in the 150 μg group, and 3·7 fold in the 500 μg group (p<0·0001). Pre-F-binding IgG remained significantly 3·2 fold above baseline in the 50 μg group, 3·4 fold in the 150 μg group, and 4·0 fold in the 500 μg group (p<0·0001). Pre-F-binding serum IgA remained 4·1 fold above baseline in the 50 μg group, 4·3 fold in the 150 μg group, and 4·8 fold in the 500 μg group (p<0·0001). Although a higher vaccine dose or second immunisation elicited a transient advantage compared with lower doses or a single immunisation, neither significantly impacted long-term neutralisation. There was no long-term effect of dose, number of vaccinations, or adjuvant on neutralising activity. In this phase 1 study, DS-Cav1 vaccination was safe and well tolerated. DS-Cav1 vaccination elicited a robust boost in RSV F-specific antibodies and neutralising activity that was sustained above baseline for at least 44 weeks. A single low-dose of pre-F immunisation of antigen-experienced individuals might confer protection that extends throughout an entire RSV season. The National Institutes of Allergy and Infectious Diseases.

Predictive factors of continuous negative extrathoracic pressure management failure in children with moderate to severe respiratory syncytial virus infection

Continuous negative extrathoracic pressure (CNEP) might be beneficial for children with severe respiratory tract infections. However, there are no available data on the predictors of its failure among individuals with respiratory syncytial virus (RSV) infections. Here, we conducted a retrospective cohort study between October 1, 2015 and October 31, 2018 in hospitalized children with moderate to severe symptoms of respiratory syncytial virus (RSV) infections. We divided 45 children requiring CNEP ventilation with a non-fluctuating negative pressure of − 12 cm H2O into two groups. They were classified based on improvement or deterioration of their respiratory disorder under CNEP ventilation (responder group: n = 27, failure group: n = 18). Based on the univariate analysis, the responder and failure groups significantly differed in terms of median age, days elapsed from RSV onset to the initiation of CNEP, white blood cell count (WBC), titer of venous pCO2, body temperature at admission, and modified Wood-Downes Score (mWDS) 6 h after initiating CNEP. Based on a logistic regression analysis adjusted for age < 1 year upon admission, less than 5 days elapsed from RSV onset to the initiation of CNEP, not high value of WBC and body temperature at admission, and high values of mWDS 6 h after initiating CNEP were found to be significant independent risk factors for CNEP ventilation failure. The former two variables were associated with less failure (odds ratio was approximately 5), and the latter two variables are associated with more failure (odds ratio was approximately 8–9). Thus, CNEP could be a valid option for children with moderate to severe RSV infections, especially in those who were aged > 1 year, and specific clinical and laboratory findings.

High frequency oscillatory ventilation and conventional mechanical ventilation in the treatment of infants with severe respiratory syncytial virus pneumonia: a randomized controlled trial

To compare the clinical efficacy of high frequency oscillatory ventilation (HFOV) and conventional mechanical ventilation (CMV) in the treatment of infants with severe respiratory syncytial virus (RSV) pneumonia. A prospective randomized controlled trial was conducted. The infants with severe RSV pneumonia who received invasive mechanical ventilation admitted to intensive care unit (ICU) of Children's Hospital Affiliated to Capital Institute of Pediatrics from January 2018 to December 2019 were enrolled. According to the order of admission, each infant was assigned to HFOV group or CMV group by random number table. The basic data, pediatric critical score, blood gas analysis, ventilator parameters, oxygenation index [OI, OI = mean airway pressure (Pmean)×fraction of inspired oxygen (FiO2)/arterial partial pressure of oxygen (PaO2)×100], duration of mechanical ventilation, length of ICU stay, complications, prognosis, use of muscle relaxants and vasoactive drugs and other clinical indicators of the two groups were recorded. A total of 28 infants were enrolled in the analysis, including 15 infants receiving CMV and 13 infants receiving HFOV. There were no significant differences in age, body weight, pediatric critical score and OI before enrollment, type II respiratory failure, multiple organ dysfunction, basic diseases and laboratory examination indexes before enrollment between the two groups. Six hours after enrollment, compared with CMV group, heart rate (HR), respiratory rate (RR), case of transcutaneous oxygen saturation (SpO2) decrease, case of HR decrease, case of cardiopulmonary resuscitation (CPR) and OI in HFOV group were significantly decreased [HR (bpm): 130 (125, 138) vs. 144 (140, 160), RR (times/min): 35 (34, 38) vs. 40 (35, 45), SpO2 decrease (case: 1 vs. 10), HR decrease (case: 0 vs. 6), CPR (case: 0 vs. 4), OI: 6.5 (4.4, 8.9) vs. 9.3 (8.0, 12.8)], while case of use of muscle relaxants (case: 3 vs. 0) and volume of 7-day positive fluid balance [mL/kg: 167.1 (113.8, 212.6) vs. 90.8 (57.8, 112.7)] were significantly higher, the differences were statistically significant (all P < 0.05). There was no use of blood purification treatment, no severe complications such as pneumothorax and intracranial hemorrhage, and no death within 28 days in the two groups. Compared with CMV, HFOV in the treatment of infants with severe RSV pneumonia can improve the oxygenation level and clinical physiological indexes earlier, reduce the incidence of adverse events such as HR, SpO2 decrease and CPR, increase the use of muscle relaxants and the positive fluid balance, and do not increase the incidence of severe complications such as pneumothorax and intracranial hemorrhage, so its clinical application is safe.