ArticleLiterature Review

Lower respiratory tract infection caused by Respiratory Syncytial Virus: current management and new therapeutics.

September 2015

DOI:10.1016/S2213-2600(15)00255-6

Authors:

Natalie Mazur

University Medical Center Utrecht

Eugenio Baraldi

University of Padua

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Respiratory syncytial virus (RSV) is a major worldwide cause of morbidity and mortality in children under five years of age. Evidence-based management guidelines suggest that there is no effective treatment for RSV lower respiratory tract infection (LRTI) and that supportive care, ie, hydration and oxygenation, remains the cornerstone of clinical management. However, RSV treatments in development in the past decade include 10 vaccines and 11 therapeutic agents in active clinical trials. Maternal vaccination is particularly relevant because the most severe disease occurs within the first 6 months of life, when children are unlikely to benefit from active immunisation. We must optimise the implementation of novel RSV therapeutics by understanding the target populations, showing safety, and striving for acceptable pricing in the context of this worldwide health problem. In this Review, we outline the limitations of RSV LRTI management, the drugs in development, and the remaining challenges related to study design, regulatory approval, and implementation.

Bronchiolitis: evidence-based management in high-risk infants in the intensive care setting

Article

Full-text available

Jun 2024

Aim Systematically review the management of infants with severe bronchiolitis in a paediatric intensive care unit (PICU) setting with a focus on high-risk infants to identify gaps in evidence-based knowledge. Methods This systematic review utilised Preferred Reporting Items for Systematic Review and Meta-analysis Protocols (PRISMA-P) to examine the literature on the PICU management of bronchiolitis in infants <24 months old. Three databases, Embase, PubMed and Medline, were searched and higher levels of evidence I, II and III were included. Results There were 455 papers reviewed and 26 met the inclusion criteria. Furthermore, 19 of these studied respiratory interventions such as positive airway pressure and oxygen delivery. The remaining 7 examined: erythropoietin, caffeine, dexamethasone, protein supplementation, ribavirin, respiratory syncytial virus immune globulin, or diuretic therapy. Of the 26 studies, 20 excluded infants with high-risk conditions. Therapies showing favourable outcomes included Heliox, prophylactic dexamethasone pre-extubation, protein supplementation, and diuretic use. Conclusions Clinical trials for bronchiolitis management frequently exclude high-risk children. Innovative study design in the future may improve access to clinical trials for the management of bronchiolitis in high-risk infants in a PICU setting. Impact Clinical trials for bronchiolitis management frequently exclude high-risk children. We review the evidence base for the management of an under-investigated patient demographic in the setting of acute bronchiolitis. Randomised controlled trials are needed to determine the efficacy of management strategies for bronchiolitis in high-risk infants in a paediatric intensive care setting.

-NC-ND license Acute bronchiolitis and respiratory syncytial virus seasonal transmission during the COVID-19 pandemic in Spain: A national perspective from the pediatric Spanish Society (AEP)

Article

Dec 2021
J CLIN VIROL

Respiratory Syncytial Virus: A Systematic Review and Meta-Analysis of Tomographic Findings (2000-2022)

Article

Full-text available

Jul 2023
Children

Human respiratory syncytial virus (RSV) is a main cause of medical referrals and hospitalizations in all infants, particularly among newborns. Nevertheless, relatively limited evidence on chest tomography (CT) findings has been collected. According to the PRISMA statement, Pubmed, Embase, and medRxiv were searched for eligible observational studies published up to 31 December 2022. Cases were categorized in children and adolescents (age < 18 years), adults and elderly (age ≥ 18 years), and immunocompromised patients, and then pooled in a random-effects model. Heterogeneity was assessed using the I2 statistics, while reporting bias was assessed by means of funnel plots and regression analysis. A total of 10 studies (217 RSV cases) were retrieved (children, 37.3%; immunocompromised, 41.0%; adults, 21.7%). The most common features were signs of organizing pneumonia (33.65%, 95% confidence interval [95% CI] 22.39–47.27), followed by septal thickening (33.19%, 95% CI 21.76–47.03), ground glass opacities (GGOs; 28.03%, 95% CI 14.69–46.82), and tree-in-bud (TIB, 27.44%, 95% CI 15.04–44.68). Interestingly, up to 16.23% (95% CI 8.17–29.69) showed normal findings, while the large majority (76.06%, 95% CI 64.81–84.56) were characterized by bilateral involvement. Studies were highly heterogeneous without substantial reporting bias. Assuming children and adolescents as reference groups, healthy adults were characterized by a higher risk ratio [RR] for septal thickening (RR 3.878, 95% CI 1.253–12.000), nodular lesions (RR 20.197, 95% CI 1.286–317.082), and GGOs (RR 2.121, 95% CI 1.121–4.013). RSV cases are rarely assessed in terms of CT characteristics. Our study identified some specificities, suggesting that RSV infections evolve heterogeneous CT features in children/adolescents and adults, but the paucity of studies recommends a cautious appraisal.

The PATH study: Preparing for the Adoption of innovative hearing THerapies

Thesis

Sep 2022

Rishi Mandavia

BACKGROUND: Innovative drug, gene and cell therapies are being developed to address the unmet clinical need of people with hearing loss. With approval for clinical use on the horizon in the next 5 years, it is essential to start preparing for the implementation of these therapies in hearing healthcare services. AIM: To provide stakeholders who develop, will use and pay for innovative hearing therapies, with a detailed understanding of the elements that influence their adoption and implementation and with practical strategies to facilitate their uptake in the UK healthcare system. METHOD: 1) To inform product development and decisions on value for money, I constructed an early health economic model with input data from literature searches and 26 interviews. 2) To characterise and understand the elements that influence the adoption and implementation of innovative hearing therapies in the UK healthcare system, I conducted 37 semi-structured interviews drawing upon insights from the early health economic model. 3) To add to this understanding, I performed a hermeneutic review of elements that influence the adoption and implementation of innovative therapies in general. 4) To integrate the findings from my thesis, I constructed a framework that maps the elements that influence innovative hearing therapy adoption and implementation, and that summarises practical strategies to facilitate uptake. RESULTS: I found that alliances between clinicians, scientists, patients, biotechnology and hearing technology companies can facilitate adoption of innovative hearing therapies, benefitting from pooled resources, diffusion networks and established market access. Timely clinician education can break down engrained clinical practices and gain clinician buy-in. Early engagement with patients can help ensure these therapies meet patient needs and generate patient and public interest, which can influence clinician uptake and policy decisions. Precision diagnostics are critical to the development and uptake of innovative hearing therapies; co-development strategies and novel regulatory pathways can accelerate their development. Accelerator organisations can help navigate healthcare systems, assist with manufacturing and distribution strategies, support clinical trialing, help develop business cases, and lobby decision makers. Additional insights revealed that novel payment strategies and robust business cases can help make procurement affordable and avoid delays in adoption. Real world data can increase confidence to take-up innovative hearing therapies, support payment strategies, early access programs and help fulfil regulatory requirements. CONCLUSION: My research has resulted in a framework that can accelerate the uptake of innovative hearing therapies across healthcare systems. Stakeholders can use my framework to gain detailed information on the processes that need to take place for adoption and implementation of these therapies as well as strategies to facilitate these processes.

Fumarprotocetraric acid and geraniin were identified as novel inhibitors of human respiratory syncytial virus infection in vitro

Article

Full-text available

Dec 2024

Introduction Respiratory syncytial virus (RSV) remains a major international public health concern. However, disease treatment is limited to preventive care with monoclonal antibodies and supportive care. In this study, natural products were screened to identify novel anti-RSV inhibitors. Methods The antiviral effect of 320 compounds on RSV in HEp-2 cells was tested using a Cytopathic effect (CPE) inhibition assay. The antiviral effect of fumarprotocetraric acid (FUM) and geraniin (GE) were confirmed by Real-time reverse transcription quantitative PCR (Real-time RT-PCR), plaque reduction test, immunofluorescence assay, and Western blot analysis. Real-time PCR was used to detect inflammatory factor expression. ATP assay and JC-1 stain were used to evaluate mitochondrial protection function. The experiment of administration time was used to determine the stages in the RSV life cycle inhibited by FUM and GE. Human metapneumovirus (HMPV) and human rhinovirus (HRV) were used to evaluate the antiviral activities of other respiratory viruses of FUM and GE. Finally, Air-liquid interface human airway epithelium (ALI-HAE) cells were used to evaluate the antiviral effect and mechanism of FUM and GE to RSV. Results The results showed that FUM and GE can inhibit the replication of RSV in multiple-cell models. Both compounds could dose-dependent inhibit the viral load, RSV nucleic acids level, and RSV-F protein level. Besides, FUM and GE showed good anti-inflammatory activity, mitochondrial protection, and antiviral activity to HMPV and HRV. Meanwhile, our result indicated that FUM and GE can inhibit RSV replication in ALI-HAE cells. Conclusions FUM and GE were identified as new inhibitors of RSV infection. At the same time, FUM and GE have anti-inflammatory activity, mitochondrial protection function, and broad-spectrum antiviral activity. These results provide evidence that FUM and GE are potential candidates for the development of novel anti-RSV drugs.

Therapeutic efficacy of JNJ-49214698, an RSV fusion inhibitor, in RSV-infected neonatal lambs

Article

Full-text available

Dec 2024
J GEN VIROL

Respiratory syncytial virus (RSV) is a leading cause of respiratory infection, hospitalization and death in infants worldwide. No fully effective RSV therapy using direct antivirals is marketed. Since clinical efficacy data from naturally infected patients for such antivirals are not available yet, animal studies are indispensable to predict therapeutic intervention. Here, we report the impact of an RSV fusion inhibitor, JNJ-49214698, on severe RSV-associated acute lower respiratory tract infection (ALRTI) in neonatal lambs. Randomized animals were treated once daily with 25 mg/kg JNJ-49214698, starting either before RSV infection, 1 day post-infection or as late as peak lung viral load on Day 3 post-infection. Treatment efficacy was assessed by scoring clinical signs of illness, development of RSV-induced gross and microscopic lung lesions and measuring virus titres in the lungs. Treatment with JNJ-49214698 was very effective in all treatment groups. Even in animals for which treatment was delayed until peak viral load was reached, a reduced amount and severity of gross and microscopic lesions, as well as RSV titres and RNA levels, were found. These results strongly suggest that treatment with small-molecule fusion inhibitors is an effective strategy to treat patients who are diagnosed with an RSV-induced ALRTI.

Relating in vivo RSV infection kinetics to host infectiousness in different age groups

Preprint

Full-text available

Nov 2024

Respiratory syncytial virus (RSV) infections are a major public health concern for pediatric populations and older adults. Viral kinetics, the dynamic processes of viral infection within an individual over time, vary across different populations. However, RSV transmission in different age groups is incompletely understood from the perspective of individual-level viral kinetics. To explore how individual viral kinetics can be related to RSV transmission, we first fitted a mathematical model to longitudinal viral kinetic data from 53 individuals in pediatric, adult, and elderly age groups using a hierarchical Bayesian framework to estimate important viral kinetic parameters. Using a probabilistic model, we then related the within-host viral load to the probability of transmission for each age group. We found that children had higher peak viral loads and longer shedding periods compared to other age groups, suggesting a higher transmission probability in children over the infectious period. We validated our findings by comparing the estimated secondary attack rate across different age groups to empirical estimates from household transmission studies. Our work highlights the importance of age-specific considerations in understanding and managing RSV infections, suggesting that age-targeted interventions will be more effective in controlling RSV transmission. Summary We utilized within-host viral load kinetics data to infer the transmission potential of RSV infection across different age groups, revealing the highest transmission probability in the pediatric group.

Both chebulagic acid and punicalagin inhibit respiratory syncytial virus entry via multi-targeting glycoprotein and fusion protein

Article

Full-text available

Nov 2024
J VIROL

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections, with no currently available small-molecule drugs that are both safe and effective. A major obstacle in antiviral drug development is the rapid emergence of drug-resistant viral strains. Targeting multiple viral compounds may help mitigate the development of resistance. Herein, we conducted a drug screening using the Antiviral Traditional Chinese Medicine Active Compound Library, aiming to identify compounds that simultaneously target the RSV fusion (F) protein, glycoprotein (G), and the host heparan sulfate proteoglycans (HSPGs). From this screening, 10 candidate compounds were identified for their ability to interact with all three targets. Among these 10 candidates, chebulagic acid (CHLA) and punicalagin (PUG) demonstrated the most potent inhibition of RSV replication. In vitro dose–response assays confirmed the antiviral efficacy of CHLA (IC50: 0.07864 µM) and PUG (IC50: 0.08065 µM). Further experiments revealed both CHLA and PUG disrupt RSV attachment and membrane fusion by targeting the RSV-F and G proteins, rather than HSPG. Notably, CHLA and PUG were found to bind to the CX3C motif of the RSV-G protein, with docking assays predicting their binding sites at cysteines 176 and 182. Additionally, CHLA enhanced the conformational stability of the RSV-F protein before fusion. In an in vivo study, both CHLA and PUG were shown to alleviate RSV-induced pulmonary pathology by reducing viral titers, mitigating lung injury, and suppressing the inflammatory responses in the lungs. Our findings suggest that CHLA and PUG hold potential as therapeutic agents for RSV infection. IMPORTANCE A significant challenge in developing anti-respiratory syncytial virus (RSV) agents is the rapid emergence of resistant viral strains. Designing drugs that target multiple viral components can effectively reduce the likelihood of developing resistant strains. In this study, we screened compounds from the Antiviral Traditional Chinese Medicine Active Compound Library, aiming to simultaneously targe the RSV fusion (F) protein, glycoprotein (G), and host heparan sulfate proteoglycans (HSPGs). Our findings revealed that chebulagic acid (CHLA) and punicalagin (PUG) significantly inhibited RSV replication both in vitro and in vivo and interacted with all three targets. Both CHLA and PUG were able to disrupt RSV attachment and membrane fusion. Mechanistically, CHLA and PUG were found to bind to the CX3C motif of the RSV-G protein, with CHLA also enhancing the conformational stability of the RSV-F protein before fusion. In conclusion, our study suggests that CHLA and PUG hold promise as therapeutic agents against RSV infection.

Cholesterol-rich lysosomes induced by respiratory syncytial virus promote viral replication by blocking autophagy flux

Article

Full-text available

Jul 2024

Respiratory syncytial virus (RSV) hijacks cholesterol or autophagy pathways to facilitate optimal replication. However, our understanding of the associated molecular mechanisms remains limited. Here, we show that RSV infection blocks cholesterol transport from lysosomes to the endoplasmic reticulum by downregulating the activity of lysosomal acid lipase, activates the SREBP2–LDLR axis, and promotes uptake and accumulation of exogenous cholesterol in lysosomes. High cholesterol levels impair the VAP-A-binding activity of ORP1L and promote the recruitment of dynein–dynactin, PLEKHM1, or HOPS VPS39 to Rab7–RILP, thereby facilitating minus-end transport of autophagosomes and autolysosome formation. Acidification inhibition and dysfunction of cholesterol-rich lysosomes impair autophagy flux by inhibiting autolysosome degradation, which promotes the accumulation of RSV fusion protein. RSV-F storage is nearly abolished after cholesterol depletion or knockdown of LDLR. Most importantly, the knockout of LDLR effectively inhibits RSV infection in vivo. These findings elucidate the molecular mechanism of how RSV co-regulates lysosomal cholesterol reprogramming and autophagy and reveal LDLR as a novel target for anti-RSV drug development.

Trends in hospitalizations of children with respiratory syncytial virus aged less than 1 year in Italy, from 2015 to 2019

Article

Full-text available

Jun 2024
Riv Ital Pediatr Ital J Pediatr

Background Respiratory syncytial virus (RSV) affects 60–80% of children below 1 year and it’s the first cause of acute bronchiolitis. The aim of this study was to assess the trend and characteristics of hospitalizations for RSV infections in Italy. Methods This is a retrospective study based on the Italian Hospital Discharge Record (HDR) database. We analysed HDRs from June 2015 to May 2019, considering two groups of infants: Group 1 had a confirmed diagnosis of RSV; Group 2 had a diagnosis of acute bronchiolitis not RSV-coded. Results There were 67,746 overall hospitalizations (40.1% Group 1, and 59.9% Group 2). Hospitalization rate increased for Group 1 from 125 to 178 per 10,000 infants (+ 42.4%), and for Group 2 from 210 to 234 per 10,000 (+ 11.4%). The mean hospitalization length was 6.3 days in Group 1, longer than Group 2 (+ 1.0 day). A further analysis revealed that infants with heart disease or born premature had longer mean hospital stay compared to infants without risk factors (10.7 days versus 6.1 days, p < 0.0001; 34.0 days versus 6.1 days, p < 0.0001, respectively). Group 1 required more critical care (oxygen therapy and/or mechanical ventilation) than Group 2. We found that, in proportion to hospital admissions in pediatric and general hospitals, RSV was more frequently diagnosed in the first ones. The mean hospitalization cost increased for Group 1 (from € 2,483 to € 2,617) and Group 2 (from € 2,007 to € 2,180). Conclusions Our results confirmed that RSV pulmonary disease in infants is seasonal and often requires hospitalization. Our study suggested that RSV is responsible for an increasing hospitalization rate and related costs during the study period.

Farnesyltransferase inhibitor lonafarnib suppresses respiratory syncytial virus infection by blocking conformational change of fusion glycoprotein

Article

Full-text available

Jun 2024

Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in young children and the elderly. There are currently no approved RSV-specific therapeutic small molecules available. Using high-throughput antiviral screening, we identified an oral drug, the prenylation inhibitor lonafarnib, which showed potent inhibition of the RSV fusion process. Lonafarnib exhibited antiviral activity against both the RSV A and B genotypes and showed low cytotoxicity in HEp-2 and human primary bronchial epithelial cells (HBEC). Time-of-addition and pseudovirus assays demonstrated that lonafarnib inhibits RSV entry, but has farnesyltransferase-independent antiviral efficacy. Cryo-electron microscopy revealed that lonafarnib binds to a triple-symmetric pocket within the central cavity of the RSV F metastable pre-fusion conformation. Mutants at the RSV F sites interacting with lonafarnib showed resistance to lonafarnib but remained fully sensitive to the neutralizing monoclonal antibody palivizumab. Furthermore, lonafarnib dose-dependently reduced the replication of RSV in BALB/c mice. Collectively, lonafarnib could be a potential fusion inhibitor for RSV infection.

Single domain antibodies from camelids in the treatment of microbial infections

Article

May 2024

Infectious diseases continue to pose significant global health challenges. In addition to the enduring burdens of ailments like malaria and HIV, the emergence of nosocomial outbreaks driven by antibiotic-resistant pathogens underscores the ongoing threats. Furthermore, recent infectious disease crises, exemplified by the Ebola and SARS-CoV-2 outbreaks, have intensified the pursuit of more effective and efficient diagnostic and therapeutic solutions. Among the promising options, antibodies have garnered significant attention due to their favorable structural characteristics and versatile applications. Notably, nanobodies (Nbs), the smallest functional single-domain antibodies of heavy-chain only antibodies produced by camelids, exhibit remarkable capabilities in stable antigen binding. They offer unique advantages such as ease of expression and modification and enhanced stability, as well as improved hydrophilicity compared to conventional antibody fragments (antigen-binding fragments (Fab) or single-chain variable fragments (scFv)) that can aggregate due to their low solubility. Nanobodies directly target antigen epitopes or can be engineered into multivalent Nbs and Nb-fusion proteins, expanding their therapeutic potential. This review is dedicated to charting the progress in Nb research, particularly those derived from camelids, and highlighting their diverse applications in treating infectious diseases, spanning both human and animal contexts.

Respiratory Syncytial Virus-Associated Hospitalizations in Children: A 10-Year Population-Based Analysis in Finland, 2008-2018

Article

Full-text available

Mar 2024
INFLUENZA OTHER RESP

Background The risk of respiratory syncytial virus (RSV) hospitalization is highest during the first months of life, but few studies have assessed the population‐based rates of hospitalization in monthly age groups of infants. Methods We determined the average population‐based rates of hospitalization with virologically confirmed RSV infections in children ≤15 years of age admitted during the 10‐year period of 2008–2018. Testing for RSV was routine in all children hospitalized with respiratory infections, and all RSV‐positive children admitted at any time during the study period were included in the analyses. Results The annual population‐based rate of RSV hospitalization was highest in infants 1 month of age (52.0 per 1000 children; 95% CI, 45.2–59.7), followed by infants <1 month of age (34.8 per 1000; 95% CI, 29.2–41.1) and those 2 months of age (32.2 per 1000; 95% CI, 26.9–38.4). In cumulative age groups, the rate of hospitalization was 39.7 per 1000 (95% CI, 36.2–43.4) among infants <3 months of age, 26.8 per 1000 (95% CI, 24.8–29.0) in infants aged <6 months, and 15.8 per 1000 (95% CI, 14.7–17.0) in those <12 months of age. Conclusion In monthly age groups of infants, the incidence rates of virologically confirmed RSV hospitalization in all infants up to 3 months of age were substantially higher than those reported in earlier studies. These data may be important for improving the estimates of the cost‐effectiveness of various interventions to reduce the burden of RSV in young infants.

Bacteria and viruses and their role in the preschool wheeze to asthma transition

Article

Full-text available

Mar 2024
PEDIATR ALLERGY IMMU

Wheezing is the cardinal symptom of asthma; its presence early in life, mostly caused by viral infections, is a major risk factor for the establishment of persistent or recurrent disease. Early‐life wheezing and asthma exacerbations are triggered by common respiratory viruses, mainly rhinoviruses (RV), and to a lesser extent, respiratory syncytial virus, parainfluenza, human metapneumovirus, coronaviruses, adenoviruses, influenza, and bocavirus. The excess presence of bacteria, several of which are part of the microbiome, has also been identified in association with wheezing and acute asthma exacerbations, including haemophilus influenza, streptococcus pneumoniae, moraxella catarrhalis, mycoplasma pneumoniae, and chlamydophila pneumonia. While it is not clear when asthma starts, its characteristics develop over time. Airway remodeling already appears between the ages of 1 and 3 years of age even prior to the presence of atopic inflammation or an asthma diagnosis. The role of genetic defect or variations hampering the airway epithelium in response to environmental stimuli and severe disease morbidity are now considered as major determinants for early structural changes. Repeated viral infections can induce and perpetuate airway hyperresponsiveness. Allergic sensitization, that often precedes infection‐induced wheezing, shifts inflammation toward type‐2, while common respiratory infections themselves promote type‐2 inflammation. Nevertheless, most children who wheeze with viral infections during infancy and during preschool years do not develop persistent asthma. Multiple factors, including illness severity, viral etiology, allergic sensitization, and the exposome, are associated with disease persistence. Here, we summarize current knowledge and developments in infection epidemiology of asthma in children, describing the known impact of each individual agent and mechanisms of transition from recurrent wheeze to asthma.

Impact of SARS-CoV2 Pandemic and Lockdown on the RSV Circulation: Experience of Three Spoke Hospitals in Northern Italy

Preprint

Full-text available

Jan 2024

The SARS-CoV2 Pandemic affected the global epidemiology of respiratory infections, including Respiratory Syncytial Virus (RSV), thanks to state governments’ implementation of mitigation strategies, like the promotion of face masks and lockdowns. However, after the Pandemic, the dramatic resurge of these diseases was reported worldwide. Our retrospective study, involving three Spoke Pediatric Departments, includes all the infants under one year of age hospitalized for RSV bronchiolitis in a period before the Pandemic period (2017-2020), during the SARS-CoV2 Pandemic (2020-2021) and after the Pandemic (2021-2023). The primary aim was to analyse the temporal trend of RSV in the three periods. Then, clinical and epidemiological characteristics were analysed to highlight clinical differences in the patients affected, in the severity of the in-fections and in the short-term outcomes. Ultimately, we analysed the RSV prevalence in the global bronchiolitis hospitalization in the same over reported periods. Overall, we included 237 patients. Before the Pandemic, the peak was recorded in January and February while after the Pandemic, the peak was in November and December. A higher prevalence of RSV was demon-strated after the Pandemic compared to the period before the Pandemic; no difference in severity was reported overall. In conclusion, an increase in RSV cases after the Pandemic has been demonstrated with an anticipated peak, while no differences were recorded in severity.

RSV Induces Activation of Intracellular EGFR on the Mitochondrial Membrane for Virus Propagation

Article

Full-text available

Dec 2023
INT J MOL SCI

Respiratory syncytial virus (RSV) infects people of all ages and is one of the most common causative agents of lower respiratory tract infections, such as pneumonia, especially in infants under one year of age. However, no direct treatment has been developed for RSV infections. Maintenance of mitochondrial homeostasis and epidermal growth factor receptor (EGFR) activity is important for human cell growth. This study reported that RSV infection maintained the total cellular ATP levels and promoted the intracellular activity of EGFR to replicate RSV. RSV activates the intracellular EGFR-mediated cell survival signaling cascade and maintains mitochondrial EGFR expression for viral production during early events after infection. The approved EGFR inhibitor, vandetanib, markedly reduces RSV propagation, suggesting that EGFR is an attractive host target for RSV therapeutics. Our results suggest that RSV infection maintains cellular ATP levels and promotes the activation of intracellular EGFR in the mitochondrial membrane, significantly contributing to robust RSV propagation.

Network pharmacology combined with metabolomics to explore the mechanism for Lonicerae Japonicae flos against respiratory syncytial virus

Article

Full-text available

Dec 2023

Background Respiratory Syncytial Virus (RSV) stands out as a primary contributor to lower respiratory tract infections and hospitalizations, particularly in infants. Lonicerae japonicae flos (LJF), a traditional Chinese medicine renowned for its efficacy against various viral infections, including RSV, has been widely employed. Despite its common use, the precise therapeutic mechanism of LJF against RSV remains elusive. This study aimed to investigate the underlying mechanism of LJF against RSV through network pharmacology and metabolomics. Methods In this study, based on network pharmacology, potential targets related to LJF and RSV were obtained from PubChem and Swiss Target Prediction. The core targets and pathways were established and verified by enrichment analysis and molecular docking. The anti-RSV efficacy of LJF was determined by in vitro experiments. Additionally, metabolomics analysis was integrated, allowing for the identification of differential metabolites and their correlation with targets following LJF treatment in the context of RSV infection. Results A total of 23 active ingredients and 780 targets were obtained, of which 102 targets were associated with LJF anti-RSV. The construction of the corresponding Protein–Protein Interaction (PPI) network unveiled potential core targets, including STAT3, TNF, and AKT1. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that LJF's anti-RSV effects primarily involve key pathways such as the PI3K-Akt signaling pathway, EGFR tyrosine kinase inhibitor resistance, and FoxO signaling pathway. Molecular docking showed that ZINC03978781, 4,5'-Retro-.beta.,.beta.-Carotene -3,3'-dione, 4',5'-didehydro and 7-epi-Vogeloside had better binding ability. The cellular assay showed that the therapeutic index of LJF against RSV was 4.79. Furthermore, 18 metabolites were screened as potential biomarkers of LJF against RSV, and these metabolites were mainly involved in the pathways of purine metabolism, linoleic acid metabolism, alpha-linolenic acid metabolism, and other related pathways. Conclusions The intergration of network pharmacology and metabolomics can clarify the active targets and related pathways of LJF against RSV, which could provide a valuable reference for further research and clinical application of LJF.

Role of Virus-Induced EGFR Trafficking in Proviral Functions

Article

Full-text available

Dec 2023

Since its discovery in the early 1980s, the epidermal growth factor receptor (EGFR) has emerged as a pivotal and multifaceted player in elucidating the intricate mechanisms underlying various human diseases and their associations with cell survival, proliferation, and cellular homeostasis. Recent advancements in research have underscored the profound and multifaceted role of EGFR in viral infections, highlighting its involvement in viral entry, replication, and the subversion of host immune responses. In this regard, the importance of EGFR trafficking has also been highlighted in recent studies. The dynamic relocation of EGFR to diverse intracellular organelles, including endosomes, lysosomes, mitochondria, and even the nucleus, is a central feature of its functionality in diverse contexts. This dynamic intracellular trafficking is not merely a passive process but an orchestrated symphony, facilitating EGFR involvement in various cellular pathways and interactions with viral components. Furthermore, EGFR, which is initially anchored on the plasma membrane, serves as a linchpin orchestrating viral entry processes, a crucial early step in the viral life cycle. The role of EGFR in this context is highly context-dependent and varies among viruses. Here, we present a comprehensive summary of the current state of knowledge regarding the intricate interactions between EGFR and viruses. These interactions are fundamental for successful propagation of a wide array of viral species and affect viral pathogenesis and host responses. Understanding EGFR significance in both normal cellular processes and viral infections may not only help develop innovative antiviral therapies but also provide a deeper understanding of the intricate roles of EGFR signaling in infectious diseases.

Respiratory Syncytial Virus: Willingness towards a Future Vaccine among Pregnant Women in Italy

Article

Full-text available

Nov 2023

Background: This cross-sectional survey was designed to evaluate pregnant women’s awareness regarding Respiratory Syncytial Virus (RSV) infection and willingness to receive the vaccine during pregnancy and to vaccinate their newborn against RSV. Methods: An anonymous survey was administered from 20 April to 30 June 2023, to pregnant women aged ≥ 18 years attending gynecology wards of randomly selected public hospitals in southern Italy. A minimum sample size of 427 participants was calculated. The survey assessed women’s socio-demographic characteristics, health-related information, their source(s) of information, and attitudes regarding RSV. Results: A total of 490 women participated. Those who were married/cohabiting, with a high-school degree compared to those who had a university degree, and those who needed additional information were more concerned that the newborn could acquire the RSV infection. The perceived utility of a future RSV vaccine administered during pregnancy was higher among those who were married/cohabiting, with a university degree, those with very good perceived health status, those who received information from healthcare workers, and those who needed additional information. Only 45.9% were willing to be vaccinated during pregnancy, and this was more likely among those with a university degree, with a very good perceived health status, who had received information from healthcare workers, and who needed more information. Finally, almost two-thirds (61.1%) were willing to vaccinate their newborn, and this was more likely among women with a university degree, with a very good perceived health status, and who needed additional information. Conclusions: An education campaign regarding RSV infection and its vaccine is needed in order to improve women’s perception and to support healthcare workers in promoting it when it will be available.

Diabetes and bacterial co-infection are two independent risk factors for respiratory syncytial virus disease severity

Article

Full-text available

Nov 2023

Diabetes mellitus (DM) is common among older adults hospitalized with lower respiratory tract infection, yet information on the impact of DM on disease severity is limited. This study retrospectively analyzed 46 Turkish patients infected with respiratory syncytial virus (RSV), with information on their comorbidities, co-infection status, and symptoms. Patients are grouped into four severity levels from mild to severe, according to lung parenchymal infiltration status and oxygen level. Similar to previously published studies, we found that comorbidities of diabetes, heart failure, hypertension, co-infection of any type, bacterial co-infection, and age are associated with the disease severity. Cough is the most common symptom (89%) followed by fever (26%) and myalgia, dyspnea, and weakness (around 20%). Using a second-order analysis (two-variable regression), we identified two independent risks for disease severity, the first is represented by diabetes, and the second is represented by bacterial co-infection. We observed two patients whose more severe symptoms were not associated with an older age, but associated with a combination of diabetes and bacterial co-infection. To confirm the true causality from the statistical correlation, further studies are needed.

Respiratory syncytial virus co-opts hypoxia-inducible factor-1α-mediated glycolysis to favor the production of infectious virus

Article

Full-text available

Oct 2023

Glycolysis, a series of oxidative reactions used to metabolize glucose and provide energy to host cells, is also required for respiratory syncytial virus (RSV) infection. However, the role of glycolysis during RSV infection and its underlying molecular mechanisms remain to be further explored. In this study, we investigated the function of hypoxia-inducible factor (HIF)-1α-mediated glycolysis in HEp-2 cells and mouse models during RSV infection. The results showed that RSV infection activated the insulin receptor (IR)-PI3K-Akt axis, upregulated the translation and activity of HIF-1α, increased the expression of glucose transporters (Glut1, Glut3, and Glut4), hexokinase (HK) 1 and 2, and platelet-type phosphofructokinase (PFKP), and promoted glucose uptake and glycolysis. In addition, mitochondrial damage induced by RSV resulted in the generation of large amounts of reactive oxygen species (ROS) in infected cells, which contributed to the stabilization and activation of HIF-1α. An energy map of the glycolytic ATP production rate (Glyco-ATP) versus the mitochondrial ATP production rate (mito-ATP) confirmed a switch from oxidative phosphorylation (OXPHOS) to glycolysis. Inhibition of IR-PI3K-Akt signaling, ROS, or HIF-1α effectively reversed the RSV-induced increase in glycolysis by blocking HIF-1α activation. Importantly, HIF-1α-mediated glycolysis provided energy for the production of progeny RSV virions. The production of infectious virions was nearly abolished after knocking down HIF-1α. PX-478, an orally active HIF-1α inhibitor, effectively inhibited RSV infection in vivo. Collectively, these results indicate the role of HIF-1α-mediated glycolysis in RSV infection and highlight HIF-1α as a potential target for anti-RSV drug development. IMPORTANCE Respiratory syncytial virus (RSV) is the leading etiological agent of lower respiratory tract illness. However, efficacious vaccines or antiviral drugs for treating RSV infections are currently not available. Indeed, RSV depends on host cells to provide energy needed to produce progeny virions. Glycolysis is a series of oxidative reactions used to metabolize glucose and provide energy to host cells. Therefore, glycolysis may be helpful for RSV infection. In this study, we show that RSV increases glycolysis by inducing the stabilization, transcription, translation, and activation of hypoxia-inducible factor (HIF)-1α in infected cells, which is important for the production of progeny RSV virions. This study contributes to understanding the molecular mechanism by which HIF-1α-mediated glycolysis controls RSV infection and reveals an effective target for the development of highly efficient anti-RSV drugs.

The epidemiologic trend of respiratory syncytial virus has returned strongly to its origin after the pandemic: Five‐year data from a single center

Article

Sep 2023

Objective Only a few studies have investigated the frequency and severity of respiratory syncytial virus (RSV) infections after the end of the pandemic regulations. This study aims to investigate the frequency and severity of RSV infections before, during, and after the pandemic in Turkey. Materials and Methods Patients under 18 years of age and those who tested positive for RSV between April 2018 and March 2023 were retrospectively reviewed. All patients were divided into three groups (pre‐COVID‐19, COVID‐19, and post‐COVID‐19) according to admission date. Among inpatients, data were compared between the three groups to determine the impact of the pandemic on RSV epidemiology and clinical outcomes. Results A total of 9567 patients were tested for RSV, of which 1073 (11.2%) were positive and included in the study. Hospitalization occurred in 447 (41.7%) patients. Inpatients were younger than outpatients ( p < .000). Among the three inpatient pandemic groups, clinical outcomes were statistically significantly worse in the post‐COVID‐19 group than in the other two groups. SpO 2 was lower ( p < .000), inhaled salbutamol requirement was higher ( p < .000), length of stay was longer ( p = .031), and ICU admission was higher ( p = .023). Conclusion Although the RSV trend changed within 2 years after the COVID‐19 outbreak, it returned to its usual seasonality last year. After the repeal of all COVID‐19 measures and the normal life began, the number of RSV‐positive patients and RSV‐related hospitalizations increased, and the clinical outcomes of RSV worsened. This may be a result of decreased herd immunity due to a change in society's attitude toward epidemic diseases.

Vaccines' New Era-RNA Vaccine

Article

Full-text available

Aug 2023

RNA vaccines, including conventional messenger RNA (mRNA) vaccines, circular RNA (circRNA) vaccines, and self-amplifying RNA (saRNA) vaccines, have ushered in a promising future and revolutionized vaccine development. The success of mRNA vaccines in combating the COVID-19 pandemic caused by the SARS-CoV-2 virus that emerged in 2019 has highlighted the potential of RNA vaccines. These vaccines possess several advantages, such as high efficacy, adaptability, simplicity in antigen design, and the ability to induce both humoral and cellular immunity. They also offer rapid and cost-effective manufacturing, flexibility to target emerging or mutant pathogens and a potential approach for clearing immunotolerant microbes by targeting bacterial or parasitic survival mechanisms. The self-adjuvant effect of mRNA-lipid nanoparticle (LNP) formulations or circular RNA further enhances the potential of RNA vaccines. However, some challenges need to be addressed. These include the technology’s immaturity, high research expenses, limited duration of antibody response, mRNA instability, low efficiency of circRNA cyclization, and the production of double-stranded RNA as a side product. These factors hinder the widespread adoption and utilization of RNA vaccines, particularly in developing countries. This review provides a comprehensive overview of mRNA, circRNA, and saRNA vaccines for infectious diseases while also discussing their development, current applications, and challenges.

Phytocompounds as a source for the development of new drugs to treat respiratory viral infections

Chapter

Jan 2023

Molecular Profiling of Inflammatory Mediators in Human Respiratory Syncytial Virus and Human Bocavirus Infection

Article

Full-text available

May 2023

Infections due to human respiratory syncytial virus (HRSV) and human bocavirus (HBoV) can mediate the release of several pro-inflammatory cytokines such as IL-6, IL-8, and TNF-α, which are usually associated with disease severity in children. In this study, the change in the expression profile of cytokines and chemokines were determined during HRSV, HBoV, and HRSV coinfection with HBoV in 75 nasopharyngeal aspirates (NPAs) samples, positive real-time reverse transcriptase PCR Assay (rRT-PCR) for HRSV (n = 36), HBoV (n = 23) infection alone or HRSV coinfection with HBoV (n = 16). The samples were collected from hospitalized children. qPCR-based detection revealed that the levels of IL-6, IL-8, IL-10, IL-13, IL-33, and G-CSF were significantly (p < 0.05) greater in patients than in controls. IL-4, IL-17, GM-CSF, and CCL-5 were significantly elevated in children with HRSV coinfection with HBoV than in other groups (p < 0.05). TNF-α, IL-6, IL-8, IL-10, IL-13, and IL-33 in children with HRSV were significantly increased in severe infections compared to mild infections. Whereas, IL-10, IL-13, and IL-33 were significantly increased in severe infection in compared a mild infection in children with HBoV. Further large-scale investigations involving isolates are needed to enhance our knowledge of the association between viral infections and cytokine expression patterns during the different stages of HRSV and HBoV infection

Viral and Atypical Pathogen's Epidemiology of a Large Cohort of Patients with Acute Respiratory Tract Infections in Shaanxi Province, Northwest China

Article

Full-text available

May 2023

Purpose To analyze and summarize the etiological and epidemiological characteristics of acute respiratory tract infections (ARIs) in northwest China to improve the clinical management and prevention of local ARIs. Methods Patients with ARIs in Shaanxi Province, from January 2014 to December 2018, were retrospectively analyzed. Indirect immunofluorescence assay (IFA) was used to detect the IgM antibody of eight respiratory pathogens. Results A total of 15,543 eligible patients were included in this study. Overall, 36.01% of the patients (5597/15543) were positive for at least one of eight pathogens, among which single and mixed infections accounted for 74.65% (4178/5597) and 25.35% (1419/5597), respectively. Mycoplasma (MP) showed the highest detection rate (18.12%), followed by influenza virus B (Flu B, 11.65%), chlamydia (CP, 7.00%), respiratory syncytial virus (RSV, 4.18%), parainfluenza virus (PIV, 2.83%), influenza virus A (Flu A, 1.69%), legionella (LP, 1.00%) and adenovirus (ADV, 0.70%). Flu B (17.54%, 759/4327) was the most prevalent virus in patients aged less than 18 years. In addition, common respiratory infections with higher detection rates were found in autumn (39.65%), followed by winter (37.37%), summer (36.21%) and spring (30.91%). There were significant differences in the detection rates of pathogens in different seasons (P < 0.001). Conclusion These findings serve as a reference for local health authorities to develop further plans for the prevention and control of ARIs.

Comparison of the Canadian vs. the international risk scoring tool for respiratory syncytial virus prophylaxis in moderate-to-late preterm infants

Article

Full-text available

Jan 2023

Aim The study objective was to compare the Pediatric Investigators Collaborative Network on Infections in Canada risk scoring tool (CRST) that determines need for respiratory syncytial virus (RSV) prophylaxis in infants 33–35 weeks gestational age during the RSV season, with the newly developed international risk scoring tool (IRST). Methods Children 33–35 weeks gestational age born during the 2018–2021 RSV seasons were prospectively identified following birth and scored with the validated CRST and IRST, that comprises seven and three variables respectively, into low- moderate- and high-risk groups that predict RSV-related hospitalization. Correlations between total scores on the two tools, and cut-off scores for the low-, moderate- and high-risk categories were conducted using the Spearman rank correlation. Results Over a period of 3 RSV seasons, 556 infants were scored. Total risk scores on the CRST and the IRST were moderately correlated ( r s = 0.64, p < 0.001). A significant relationship between the risk category rank on the CRST and the risk category rank on the IRST ( r s = 0.53; p < 0.001) was found. The proportion of infants categorized as moderate risk for RSV hospitalization by the CRST and IRST were 19.6% ( n = 109) and 28.1% ( n = 156), respectively. Conclusion The IRST may provide a time-efficient scoring alternative to the CRST with three vs. seven variables, and it selects a larger number of infants who are at moderate risk for RSV hospitalization for prophylaxis. A cost-utility analysis is necessary to justify country-specific use of the IRST, while in Canada a cost comparison is necessary between the IRST vs. the currently approved CRST prior to adoption.

Infodemiology of RSV in Italy (2017-2022): An Alternative Option for the Surveillance of Incident Cases in Pediatric Age?

Article

Full-text available

Dec 2022
Children

The aim of this study was to evaluate whether or not online queries for Respiratory Syncytial Virus (RSV) retrieved by means of Google Trends™ and the Italian Wikipedia analysis program mirror the occurrence of influenza-like illnesses (ILI), as reported by the Italian Influenza Surveillance network (InfluNet). Estimated rates for ILI in the general population and in the age groups 0-4 years and 5-14 years were obtained for the influenza seasons 2017-2018 to 2020-2021. Similarly, a weekly fraction of online searches was retrieved for a series of terms associated with Respiratory Syncytial Virus. Next, trends for daily visualization of Italian Wikipedia Pages for Human Respiratory Syncytial Virus, Pneumonia, Bronchiolitis, Influenza, and Respiratory Failure were similarly retrieved. The correlation of all search terms with ILI was analyzed by means of Spearman's rank correlation analysis. Among search terms associated with the clinical diagnosis of Respiratory Syncytial Virus infections, the occurrence of ILI was highly correlated only with Bronchiolitis in the age group 0-4 years (β 0.210, p = 0.028), while more generic search terms, such as Bronchitis, fever, influenza, and Pneumonia, were identified as effective predictors of ILI, in general and by age groups. In a regression analysis modeled with ILIs as the outcome variable, daily visualizations for the Wikipedia pages on Bronchiolitis were identified as negative predictors for ILI in general (β = −0.152, p = 0.032), ILI in age group 0-4 years (β = −0.264, p = 0.001) and 5-14 years (β = −0.202, p = 0.006), while Influenza was characterized as a positive effector for ILIs in the age group 5-14 years (β = 0.245, p = 0.001). Interestingly, not only were the search terms extensively correlated with one another, but all of them were also characterized by autocorrelation through a Durbin-Watson test (all estimates DW < 2.0) In summary, our study identified a complicated pattern of data visualization as no clear association between rates of ILI in pediatric age group 0-4 and 5 to 14 years was actually found. Finally, our data stress that the infodemiology option may be quite problematic for assessing the time trend of RSV infections in Italy until more appropriate reporting will be made available, by sharing estimates of Lower Respiratory Tract Infections, and through a more accurate characterization of younger age groups.

ON-1 and BA-IX Are the Dominant Sub-Genotypes of Human Orthopneumovirus A&B in Riyadh, Saudi Arabia

Article

Full-text available

Dec 2022

Human orthopneumovirus (HOPV) is the major viral pathogen responsible for lower respiratory tract infections (LRTIs) in infants and young children in Riyadh, Saudi Arabia. Yet, predominant HOPV subtypes circulating in this region and their molecular and epidemiological characteristics are not fully ascertained. A total of 300 clinical samples involving nasopharyngeal aspirates (NPAs), throat swabs, and sputum were collected during winter seasons of 2019/2020 and 2021/2022 for HOPV subtyping and genotyping. Of the 300 samples, HOPV was identified in 55 samples (18.3%) with a distinct predominance of type A viruses (81.8%) compared to type B viruses (18.2%). Importantly, the ON1 strain of HOPV-A and BA-IX strain of HOPV-B groups were found to be responsible for all the infections. Sequence analysis revealed a duplication region within 2nd HVR of G protein gene of ON1 and BA-IX strains. This nucleotide duplication exerted a profound effect on protein length and affinity towards cell receptors. Further, these modifications may aid the HOPV in immune evasion and recurrent infections. Data from this study showed that ON-1 genotype of HOPV-A and BA-IX genotype of HOPV-B were dominant in Riyadh, Saudi Arabia. Further, a duplication of sequence within 2nd HVR of G protein gene was found.

Nucleoside analogs for management of respiratory virus infections: mechanism of action and clinical efficacy

Article

Dec 2022

The COVID-19 pandemic has accelerated the development of nucleoside analogs to treat respiratory virus infections, with remdesivir being the first compound to receive worldwide authorization and three other nucleoside analogs (i.e. favipiravir, molnupiravir, and bemnifosbuvir) in the pipeline. Here, we summarize the current knowledge concerning their clinical efficacy in suppressing the virus and reducing the need for hospitalization or respiratory support. We also mention trials of favipiravir and lumicitabine, for influenza and respiratory syncytial virus, respectively. Besides, we outline how nucleoside analogs interact with the polymerases of respiratory viruses, to cause lethal virus mutagenesis or disturbance of viral RNA synthesis. In this way, we aim to convey the key findings on this rapidly evolving class of respiratory virus medication.

Evaluating the Antiviral Effectiveness of Different Medications in Treating Respiratory Conditions: A Thorough Meta-analysis of Drug Interventions for Acute Bronchiolitis and Bronchitis

Article

Jan 2025

Background Bronchiolitis, predominantly associated with respiratory syncytial virus (RSV), is a major cause of acute lower respiratory tract infections. Recent studies underscore RSV’s significant impact, challenging previous assumptions and revealing associations with other respiratory viruses. Despite its prevalence, current treatments for bronchiolitis are primarily supportive, with no routine use of specific antiviral drugs. Similarly, acute bronchitis, affecting 5% of adults annually, is primarily caused by viruses, with Mycoplasma pneumoniae and potential contributions from Chlamydia pneumoniae as non-viral agents. The distinct aetiologies of bronchiolitis and acute bronchitis emphasise the need for a nuanced approach to their management and further research to enhance understanding and treatment strategies. Objective The objective of this meta-analysis is to systematically assess the antiviral capabilities of different drugs, aiming to offer evidence-based insights into their effectiveness for treating patients with acute bronchiolitis and bronchitis. Materials and Methods Statistical analyses were conducted using R software 4.2.2, including mean differences (standard deviation) with a 95% confidence interval (CI) for continuous outcomes. Heterogeneity was assessed using Cochrane Q P value and I ² statistic with both random-effects and common effect models. Publication bias was evaluated through funnel plots and Egger’s regression test. Results The meta-analysis demonstrates a significant positive impact of antiviral medication on acute bronchitis, with a mean difference of 5.4027 (95% CI: 4.5771–6.2283, P < 0.0001). However, substantial heterogeneity amongst studies ( P < 0.001) emphasises the need for further exploration into sources of variation. A cautious interpretation, considering study characteristics, is crucial for a comprehensive understanding. Conclusion The meta-analysis indicates a significant positive effect of antiviral medication on acute bronchitis. However, the presence of notable heterogeneity amongst the studies emphasises the need for careful interpretation and further exploration into potential sources of variation. Despite these challenges, the findings suggest the potential efficacy of antiviral medication in treating acute bronchitis, providing valuable insights for clinical practice.

Cystic Fibrosis

Article

Apr 2023

Acute viral bronchiolitis

Chapter

Jan 2021

Severe respiratory syncytial virus infection in children: burden, management, and emerging therapies

Article

Sep 2024
LANCET

Clinical comparison of HMPV and RSV infections in hospitalised Malaysian children: A propensity score matched study

Article

Full-text available

Mar 2024
CLIN RESPIR J

Introduction Human metapneumovirus (hMPV) and respiratory syncytial virus (RSV) are significant contributors to the burden of acute respiratory infections in children, but data on hMPV from Southeast Asia are limited despite its potential for serious disease. This study aimed to compare the clinical presentation, resource utilisation and outcomes between hMPV and RSV infections in hospitalised Malaysian children. Methods This retrospective, observational study included children aged ≤12 years old hospitalised with hMPV or RSV, confirmed via direct fluorescent antibody (DFA) methods, between 1 July to 30 October 2022 at Hospital Tuanku Ja'afar Seremban, Malaysia. Demographic, clinical presentation, resource utilisation and outcome data were analysed. Propensity score matching was used to balance cohorts based on key demographic and clinical characteristics. Results This study included 192 patients, comprising 112 with hMPV and 80 with RSV. hMPV patients were older (median age 20.5 vs. 9.4 months, p < 0.001) and had a higher incidence of comorbidities (24.1% vs. 7.5%, p = 0.003). Fever was more common in the hMPV group (97.3% vs. 73.8%, p < 0.001), but the other clinical manifestations were similar. Postmatching analysis showed higher corticosteroid use in the hMPV group (p = 0.01). No significant differences were observed in the use of other resources, PICU admissions, duration of hospitalisation or mortality rates between both groups. Conclusion hMPV and RSV infections in children share similar clinical manifestations and outcomes, with hMPV affecting older children and showing higher corticosteroid usage. These findings emphasise the need for equal clinical vigilance for both hMPV and RSV in paediatric respiratory infections.

Respiratuar Sinsityal Virüse Bağlı Alt Solunum Yolu Enfeksiyonu Nedeniyle Hastanede Yatmış Çocukların Uzun Dönem Prognozunun BelirlenmesiDetermination of The Long Term Prognosis in Children Hospitalized With Lower Respiratory İnfection Due To Respiratory Syncytial Virus

Article

Feb 2024

Amaç Solunum enfeksiyonları, özellikle Respiratuvar Sinsityal Virüs (RSV), küresel olarak genç çocukları önemli ölçüde etkilemekte, ölümlere ve uzun süreli solunum sorunlarına neden olmaktadır. Erken yaşta ciddi enfeksiyonlar, yetişkinlikte astım ve bozulmuş akciğer fonksiyonu gibi kronik durumlara yol açabilir. Bu çalışma, RSV kaynaklı alt solunum yolu enfeksiyonu geçiren çocukların uzun vadeli sağlık sonuçlarını belirlemeyi amaçlamaktadır. Gereç ve Yöntemler Çocuk Sağlığı ve Hastalıkları Kliniği'nde retrospektif gözlemsel bir araştırma olarak yapılan bu çalışmada, RSV kaynaklı alt solunum yolu enfeksiyonları nedeniyle Ocak 2007 ile Aralık 2014 yılları arasında tedavi edilen 1 ay ile 5 yaş arası çocuklar incelenmiştir. Hastaların aileleri telefonla ulaşılarak bilgilendirilmiş ve sözlü onamları alınmıştır. Ardından, bu ailelerle RSV enfeksiyonundan sonraki döneme odaklanan anketler yapılmıştır. Hastaneye yatırılma risk faktörlerini belirlemek için lojistik regresyon analizi kullanılmış, istatistiksel anlamlılık p

Experts' Consensus on the Management of Respiratory Disease Syndemic

Article

Full-text available

Feb 2024

Epidemiological shifts in bronchiolitis patterns and impact of the COVID-19: A two-season comparative study

Article

Feb 2024
PEDIATR PULM

Background Bronchiolitis is a common lower respiratory tract infection (LRTI) affecting infants and young children. Respiratory syncytial virus (RSV) has historically been the primary causative agent, but other viruses also contribute to the LRTI epidemiology. Recent changes in epidemiology and clinical patterns due to the coronavirus disease 2019 (COVID‐19) pandemic have raised concerns. This study aims to analyze the impact of the pandemic on bronchiolitis epidemiology and severity. Methods Two consecutive bronchiolitis seasons (October 2021 to March 2022 and October 2022 to March 2023) were compared. Data on viral agents, hospitalization duration, clinical severity, and respiratory support requirements were collected from pediatric patients at San Marco Hospital, University of Catania. Results In the 2021–2022 season, RSV was the predominant virus (40%), followed by other viruses, with mild clinical outcomes. In the 2022–2023 season, RSV remained prevalent (58.7%), but other viruses, including rhinovirus (RV) and influenza, showed a significant increase ( p < .05) in bronchiolitis cases and severity. Notably, RSV‐related bronchiolitis did not exhibit greater severity compared to non‐RSV cases in the 2022–2023 season, contrary to the previous year. Conclusion The COVID‐19 pandemic appears to have shifted the epidemiological landscape of bronchiolitis, with a peak incidence in November instead of January/February. Non‐RSV viruses (RV, influenza A and B, as well as metapneumovirus) have gained prominence, possibly due to viral competition and reduced pandemic‐related restrictions. Traditionally, RSV has been the primary pathogen responsible for most bronchiolitis cases. Nonetheless, the findings of this study indicate a shifting landscape in bronchiolitis etiology, with RSV gradually diminishing in its role. Contrary to the previous year, RSV‐related bronchiolitis did not exhibit greater severity compared to non‐RSV cases in the 2022–2023 season.

Drug repurposing screen identifies lonafarnib as respiratory syncytial virus fusion protein inhibitor

Article

Full-text available

Feb 2024

Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory tract infection in infants, older adults and the immunocompromised. Effective directly acting antivirals are not yet available for clinical use. To address this, we screen the ReFRAME drug-repurposing library consisting of 12,000 small molecules against RSV. We identify 21 primary candidates including RSV F and N protein inhibitors, five HSP90 and four IMPDH inhibitors. We select lonafarnib, a licensed farnesyltransferase inhibitor, and phase III candidate for hepatitis delta virus (HDV) therapy, for further follow-up. Dose-response analyses and plaque assays confirm the antiviral activity (IC50: 10-118 nM). Passaging of RSV with lonafarnib selects for phenotypic resistance and fixation of mutations in the RSV fusion protein (T335I and T400A). Lentiviral pseudotypes programmed with variant RSV fusion proteins confirm that lonafarnib inhibits RSV cell entry and that these mutations confer lonafarnib resistance. Surface plasmon resonance reveals RSV fusion protein binding of lonafarnib and co-crystallography identifies the lonafarnib binding site within RSV F. Oral administration of lonafarnib dose-dependently reduces RSV virus load in a murine infection model using female mice. Collectively, this work provides an overview of RSV drug repurposing candidates and establishes lonafarnib as a bona fide fusion protein inhibitor.

Impact of SARS-CoV-2 Pandemic and Lockdown on the HRSV Circulation: Experience of Three Spoke Hospitals in Northern Italy

Article

Full-text available

Feb 2024

The SARS-CoV-2 Pandemic affected the global epidemiology of respiratory infections, including Human Respiratory Syncytial Virus (HRSV), thanks to state governments’ implementation of mitigation strategies, like the promotion of face masks and lockdowns. However, after the Pandemic, the dramatic resurge of these diseases was reported worldwide. Our retrospective study, involving three Spoke Pediatric Departments, includes all the infants under one year of age hospitalized for HRSV bronchiolitis in a period before the Pandemic period (2017–2020), during the SARS-CoV-2 Pandemic (2020–2021), and after the Pandemic (2021–2023). The primary aim was to analyze the temporal trend of HRSV in these three periods. Then, the clinical and epidemiological characteristics were analyzed to highlight the clinical differences in the affected patients, in the severity of the infections, and in the short-term outcomes. Ultimately, we analyzed the HRSV prevalence in the global bronchiolitis hospitalization over the reported periods. Overall, we included 237 patients. Before the Pandemic, the peak was recorded in January and February, while after the Pandemic, the peak was in November and December. A higher prevalence of HRSV was demonstrated after the Pandemic compared to the period before the Pandemic; overall, no difference in severity was reported. In conclusion, an increase in HRSV cases after the Pandemic has been demonstrated with an anticipated peak, while no differences were recorded in severity.

TRATAMIENTO KINÉSICO EN BRONQUIOLITIS AGUDA: ACERCA DEL ARTÍCULO PUBLICADO EN NEUMOLOGÍA PEDIÁTRICA 2016;11(2):65-70: “ACTUALIZACIÓN EN EL TRATAMIENTO DE BRONQUIOLITIS AGUDA: MENOS ES MÁS”N/A

Article

Full-text available

Oct 2021

Respiratory viral infection and resolution of inflammation: Roles for specialized pro-resolving mediators

Article

Oct 2023

Respiratory viral infections with influenza A virus (IAV) or respiratory syncytial virus (RSV) pose a significant threat to public health due to excess morbidity and mortality. Dysregulated and excessive inflammatory responses are major underlying causes of viral pneumonia severity and morbidity, including aberrant host immune responses and increased risk for secondary bacterial infections. Currently available antiviral therapies have not substantially reduced the risk of severe viral pneumonia for these pathogens. Thus, new therapeutic approaches that can promote resolution of the pathogen-initiated inflammation without impairing host defense would represent a significant advance. Recent research has uncovered the potential for specialized pro-resolving mediators (SPMs) to transduce multipronged actions for the resolution of serious respiratory viral infection without increased risk for subsequent host susceptibility to bacterial infection. Here, we review recent advances in our understanding of SPM production and SPM receptor signaling in respiratory virus infections and the intriguing potential of harnessing SPM pathways to control excess morbidity and mortality from IAV and RSV pneumonia.

RSV infection in children hospitalised with severe lower respiratory tract infection in a low-middle-income setting: A cross-sectional observational study

Article

Full-text available

Sep 2023
PLOS ONE

Introduction Low- and middle-income countries carry the largest burden of Respiratory syncytial virus (RSV) disease, with most deaths occurring in these settings. This study aimed to investigate the burden of RSV disease in South African children hospitalised with lower respiratory tract infection (LRTI), with specific reference to incidence, risk factors, and co-infections. Methods A database from a previous prospective study containing demographic, laboratory and clinical data on children hospitalised with LRTIs in Cape Town, South Africa, was used. A nasopharyngeal swab (NP) and induced sputum (IS) were tested for RSV PCR. Descriptive statistics were used to characterise the study population, and a multivariable analysis of risk factors and co-infections was done. Results RSV was detected in 142 (30.9%; 95% CI 26.7–35.3) of the included 460 study children with LRTI. The median age of RSV-positive children was 4.6 (IQR 2.4–9.7) months compared to RSV-negative children of 10.5 (IQR 4.4–21.3) months, P = <0.001. Most cases occurred in autumn and winter with 126 (89%) cases over this period. IS demonstrated greater sensitivity for RSV diagnosis with 135 cases (95.1%) detected on IS and 57 cases (40.1%) identified on NP; P<0.001. The median length of hospital stay was 3.3 (SD 4.2) days in the RSV positive group and 2.7 (SD 3.3) days in the RSV negative group; P<0.001. The median number of detected viral pathogens was 1 (IQR 0–2) in RSV-positive children (when RSV was excluded from the count) compared to 2 (IQR 2–3) in RSV negative children; P<0.001. The presence of RSV was independently associated with a reduction in the frequency of most viruses tested for on PCR. Conclusions RSV is common in children hospitalised with LRTI and mainly affects younger children. There is an urgent need to find an effective vaccine to prevent RSV pneumonia in children worldwide, especially in LMICs that carry the greatest burden of disease.

Targeting peptide‐mediated interaction between the N‐protein and P‐protein of human pediatric respiratory syncytial virus by molecular design of chemically stapled helical peptides

Article

Jul 2023

Background Human respiratory syncytial virus (hRSV) is a leading viral etiologic agent of pediatric lower respiratory infection in infants, young children, and immunocompromised elderly individuals. Objective Targeting the intermolecular interaction between the viral nucleocapsid protein (N‐protein) and phosphoprotein (P‐protein) has been recognized as a promising therapeutic strategy against hRSV infection, which is a so‐called peptide‐mediated protein/protein interaction (PmPPI) by binding the short C‐terminal tail of P‐protein to the globular domain of N‐protein. Methods The PmPPI dynamics behavior and thermodynamics property were investigated systematically by integrating computational simulations and experimental assays. Results It is revealed that the C‐terminal tail of P‐protein is intrinsically disordered in free state but would fold into a structured helix when binding to N‐protein, known as coupled folding‐upon‐binding, thus incurring a considerable entropy penalty upon the binding. Several flexible P‐peptide segments with different lengths were derived from the C‐terminus of P‐protein and then stapled chemically by using an all‐hydrocarbon bridge, which effectively constrained the peptide disordered conformation into an ordered helical form in free state, thus considerably improving their affinity to N‐protein by minimizing the unfavorable entropy penalty. Conclusions Electrostatic contribution is primarily responsible for N/P complex stability, while other noncovalent factors such as hydrogen bond and aromatic stacking confer specificity to the complex recognition. The Phe241 residue at the C‐terminal end of P‐protein plays a crucial role that anchors the flexible C‐terminal tail of P‐protein to a druggable pocket on N‐protein surface.

Exploring the adoption of less restricted criteria for respiratory syncytial virus prophylaxis in late preterm infants: insights from a retrospective analysis

Article

Full-text available

Jun 2023

Background: Preterm infants born between 33 and 35 weeks of gestational age (wGA) have been considered a “major underserved population” and ineligible to receive palivizumab (PLV), the only drug authorized to date for respiratory syncytial virus (RSV) prophylaxis, by current international guidelines. In Italy, such a vulnerable population is currently eligible for prophylaxis, and, in our region, specific risk factors are taken into consideration (SINLazio score) to target prophylaxis for those at highest risk. Whether the adoption of less or more restrictive eligibility criteria for PLV prophylaxis would translate into differences in bronchiolitis and hospitalization incidence is not known. Materials and methods: A retrospective analysis was conducted in 296 moderate-to-late preterm infants (born between 33 and 35+6 weeks) who were being considered for prophylaxis in two epidemic seasons: 2018–2019 and 2019–2020. The study participants were categorized according to both the SINLazio score and the Blanken risk scoring tool (BRST), which was found to reliably predict RSV-associated hospitalization in preterm infants on the basis of three risk factor variables. Results: Based on the SINLazio score, approximately 40% of infants (123/296) would meet the criteria to be eligible for PLV prophylaxis. In contrast, none of the analyzed infants would be considered eligible for RSV prophylaxis on the basis of the BRST. A total of 45 (15.2%) bronchiolitis diagnoses were recorded on average at 5 months of age in the overall population. Almost seven out of 10 (84/123) patients exhibiting ≥3 risk factors to be eligible for RSV prophylaxis according to SINLazio criteria would not be receiving PLV if they were categorized on the basis of the BRST. Bronchiolitis occurrence in patients with a SINLazio score ≥3 was approximately 2.2 times more likely than that in patients with a SINLazio score <3. PLV prophylaxis has been associated with a 91% lower risk of requiring a nasal cannula. Conclusion: Our work further supports the need for targeting late preterm infants for RSV prophylaxis and calls for an appraisal of the current eligibility criteria for PLV treatment. Therefore, adopting less restrictive criteria may ensure a comprehensive prophylaxis of the eligible subjects, thus sparing them from avoidable short- and long-term consequences of RSV infection. 1. Introduction Globally, respiratory syncytial virus (RSV) contributes substantially to the burden of morbidity and mortality in children of ≤5 years of age, with the occurrence of over 30 million RSV-associated acute lower respiratory tract infection (LTRI) episodes, one-tenth of which leads to hospitalization (1). In infants (0–12 months of age), a higher risk of RSV-associated hospitalization has been reported, with almost one in five infants experiencing RSV-associated LTRI being admitted to hospital (1–3). Infants who experience RSV infection in the first months of life often require intensive care unit (ICU) admission and are at risk of developing wheezing and asthma (4). Therefore, aside from the currently available therapeutic measures that are mostly supportive, preventing RSV infection is relevant to reduce both the associated morbidity and the substantial economic burden of the long-term complications of RSV disease (5). Palivizumab (PLV) is the only licensed immuno-prophylaxis available to prevent severe RSV LTRI in specific high-risk pediatric populations. In Italy, reimbursement criteria for PLV include the following: infants born at 29 weeks of gestational age (wGA) or less and less than 12 months of age, infants born at 35 wGA or less and less than 6 months of age, children less than 2 years of age and requiring treatment for bronchopulmonary dysplasia (BPD) within the last 6 months, and children less than 2 years of age and with hemodynamically significant congenital heart disease at the onset of the RSV season (6). Infants born at 34–36 completed gestational weeks account for most preterm infants: overall, in Italy, premature babies are equal to 6.3% of the total newborns in 2020; in detail, 0.7% 32–33 wGA, 4.8% 34–36 wGA (7). Compared with full term infants (≥37 wGA), late preterm (34–36 wGA) infants exhibit higher neonatal morbidity and mortality with an increased healthcare burden (8). Mounting evidence suggests that infants born between 33 and 35 wGA have a higher risk of hospitalization due to RSV infections than full-term infants (9, 10), but comparable to that seen in very preterm infants (11) with a greater ICU and hospital length of stay and higher rates of medical complications, intubation rates, and healthcare costs than infants in any other gestational age group (12). Since moderate-to-late preterm infants (33–36 wGA) constitute most of the preterm births on neonatal care, they should not be disregarded when RSV prevention interventions are implemented (8). Interrupted lung development and an immature immune system have been linked to an increased susceptibility to RSV LRTI, along with other environmental, social, and physiological risk factors. In addition, preterm infants have deficiencies in both innate and adaptive immunity, and in the interaction between these two systems (13, 14). However, despite being such a vulnerable population, the late preterm was not included in the American Academy of Pediatrics (AAP) 2014 guidelines for prophylaxis with PLV (15). Of note, when, in line with AAP guidelines, the Italian Drug Agency (AIFA) modified the indication for financial coverage in 2016 (16) by limiting it to infants with ≤29 wGA and infants with BPD born <32 wGA, a rising trend in rates of bronchiolitis and bronchiolitis-related hospitalization has been reported by several Italian hospitals, including our unit (17). When the reimbursement restrictions for infants born at GA 30– ≤35 weeks were subsequently removed by AIFA in late 2016, the proportion of infants experiencing bronchiolitis declined significantly (26% vs. 10.7%, p = 0.048), as all eligible infants could receive PLV prophylaxis (18). To effectively tackle RSV burden, it is desirable to identify the vulnerable set of infants at risk of severe infection and eligible for intervention, thus sparing them an avoidable bronchiolitis and potential hospitalization. However, a big debate as to which type of patients should receive RSV prophylaxis is ongoing, with heterogeneous recommendations being made for PLV prophylaxis among countries and a mounting body of evidence exploring the appropriateness of prophylaxis in preterm infants of ≥29 wGA (19, 20). The use of risk factors may provide a pragmatic approach to targeting prophylaxis for preterm infants at highest risk. Recently, a scoring tool [the Blanken Risk Scoring Tool (BRST)] was proposed to reliably predict the risk of RSV-associated hospitalization in moderate-late preterm infants (32–35 wGA), on the basis of three risk factor variables (21). However, such a tool has been developed on the basis of a dataset prepared from six individual studies with different objectives and design, which influenced the included gestational age ranges of infants and how and what risk factors were collected. In Italy, prophylaxis with PLV is supervised by the Italian Neonatology Society guidelines (22), which allows each region to tailor national recommendations to specific local needs. In the Lazio region, PLV prophylaxis is recommended to be started on November 1st in infants with 33–35 wGA and aged <6 months at the beginning of the epidemic RSV season, with at least, or more than, three of the following risk factors: male gender; smoking exposure; surfactant therapy; siblings <10 years old; living in crowded conditions and/or in unhealthy households and early childcare (23). Our hospital ranks first in the Lazio region, with 4,294 deliveries recorded in 2020 (24, 25). The aim of our retrospective analysis was to investigate whether the adoption of less or more restricted eligibility criteria for PLV prophylaxis would translate into differences in bronchiolitis and hospitalization incidence in late preterm infants (born between 33 and 35+6 wGA) who have not been found eligible for prophylaxis so far by international guidelines. 2. Materials and methods This is a retrospective analysis of the epidemiologic and clinical information of late preterm infants born between 2018 and 2020 and diagnosed with RSV infection at our site. Infants with the following criteria were included: (1) born at our unit (Neonatology-NICU Casilino General Hospital, Rome, Italy); (2) born during or 6 months before the two consecutive epidemic seasons 2018–2019 and 2019–2020; (3) moderate-to-late preterm born at 33–35+6. Infants with any of the following criteria were excluded: (1) BPD, (2) cystic fibrosis or congenital heart disease, (3) Down syndrome, (4) anatomic pulmonary abnormalities, and (5) neuromuscular disorders. Figure 1 illustrates a flowchart of participants in the study. The study participants were categorized according to both the SINLazio and Blanken scores. The SINLazio score is defined according to the previously described regional guidelines (23), while the BRST is calculated on the basis of the risk scoring tool previously described (21). Figure 2 illustrates the risk factors taken into consideration in both the BRST and the SINLazio score. The BRST has a scale of 0–56 with defined cutoff values for low- (≤19), moderate- (20–45), and high-risk (≥50) infants. According to the BRST, infants with moderate risk are candidates for PLV. Infants received PLV 15 mg/kg in monthly dose courses over their first epidemic season (from November to March) according to existing protocols (SINLazio) and guidelines. Along with the assessment of risk factors, the following data were also collected for each patient when applicable: (1) onset of bronchiolitis; (2) age of onset; (3) hospitalization; (4) need of respiratory support; (5) doses of PLV before admission. Informed signed consent was obtained from the parents of all infants. This pilot retrospective analysis (ID number 150.22) was approved by the Ethics committee “Lazio 2” (Report number protocol. 0011318/2023 number. 0226066 of 21/11/2022). FIGURE 1 www.frontiersin.org Figure 1. Flowchart of the participants in the study. BPD, bronchopulmonary dysplasia. FIGURE 2 www.frontiersin.org Figure 2. The risk factors taken into consideration in the Blanken Risk Scoring Tool (BRST) and in the SINLazio score. In the BRST, each risk factor has a specific score. Adding up all the scores, an infant can be grouped into one of three identified categories (low, moderate, and high for RSV Hospitalization-RSVH-) (21). According to the SINLazio score, infants with the presence of three or more risk factors need prophylaxis (23). 2.1. Statistical analysis Continuous variables were given as means with standard deviations (SD) and categorical variables as the number of subjects and percentage values. Based on the results from the derived contingency tables, sensitivity, specificity, and accuracy were calculated for the categorical SINLazio score and BRST. The association among the categorical characteristics was assayed using Pearson's χ2 test (where appropriate, using Fisher's exact test). Moreover, univariate Penalised Logistic models were used to screen the effect of demographic–clinical characteristics on bronchiolitis, hospitalization, and hospital complications (the nasal cannulas, high flows, and O2 therapy, respectively). The odd ratios associated with outcomes were calculated with their 95% confidence interval for each factor from the Penalised Logistic model. The likelihood ratio test was used as the test of statistical significance. Due to the nature of the analysis, a pilot study in this case, the correction for multiple comparisons was not performed. Differences, with a p-value of less than 0.05, were considered significant, and data were acquired and analyzed in a R v4.0.3 software environment (26). 3. Results 3.1. Demographic and clinical data The clinical data of 296 infants were retrospectively analyzed. The demographic and clinical characteristics of the study participants are illustrated in Table 1. Briefly, the mean GA and birth weight were 34.61 weeks (±1.2) and 2,230.45 grams (±410.56), respectively. A slightly greater proportion of infants were male [159/296 (53.7%)]. Approximately one-third of infants received PLV prophylaxis (94/296). TABLE 1 www.frontiersin.org Table 1. Baseline demographic and clinical characteristics of study participants (n = 296). 3.2. SINLazio score vs. BRST: differences in selecting patients eligible for PLV prophylaxis Based on the SINLazio score, approximately 40% of all analyzed infants (123/296) would meet the criteria to be eligible for PLV prophylaxis. Twenty-nine patients eligible for prophylaxis according to the SIN score did not receive the drug for different reasons, including failure of their parents to give consent for drug administration and transfer outside of the Lazio region. In contrast to the SINLazio score results, none of the analyzed infants would be considered at high risk (i.e., eligible for RSV prophylaxis based on international guidelines) according to the BRST, as most of them (173/296) displayed the lowest cutoff value (≤19), with only some having a moderate (20–45) cutoff value (48/296). A total of 45 (15.2%) bronchiolitis diagnoses were recorded on average at 5 months of age in the overall population. Despite a significant association reported between the SINLazio score and the BRST (p < 0.0001) (Table 2), almost 68.3% (84/123) of patients exhibiting ≥3 risk factors, and therefore eligible for RSV prophylaxis according to SINLazio criteria, would not be receiving PLV if they were categorized on the basis of the BRST. TABLE 2 www.frontiersin.org Table 2. Association between SINLazio score and BRST among study participants (n = 296). 3.3. SINLazio score and its association with bronchiolitis occurrence To evaluate whether the SINLazio criteria would also be informative in assessing the vulnerability of late preterm to RSV infection and therefore discriminating infants prone to bronchiolitis from healthy ones, we determined the accuracy, sensitivity, and specificity of the SINLazio score. The SINLazio score showed an accuracy rate of 61.81% [accuracy (95% CI): 61.81% (54.99%: 66.41%)] with a sensitivity and specificity of 61.35% and 57.78%, respectively. Of note, the BRST had an accuracy rate of 75.34% [accuracy (95% CI): 75.34% (70.02%: 80.14%)] with a sensitivity and specificity of 84.86% and 22.22%, respectively. A univariate analysis was performed in both the entire population (n = 296, Table 3) and in infants with symptoms distinctive of bronchiolitis (n = 45, Table 4) to evaluate whether categorizing infants with the SINLazio score would translate into differences in neonatal outcomes such as bronchiolitis and hospitalization incidence. In line with previously reported gender-related differences in RSV-related bronchiolitis (20), six out of ten (62.2%) males experienced bronchiolitis compared with less than four out of ten (37.7%) females who exhibited a 33% lower risk of having bronchiolitis [OR (95% CI) = 0.67 (0.35: 1.27)] than males. The univariate penalized logistic regression analysis (Table 3) demonstrated a significant association between the SINLazio score and the bronchiolitis event (p-value = 0.0175). In detail, bronchiolitis occurrence in patients with a SINLazio score ≥3 was approximately 2.2 times more likely than that in patients with a SINLazio score <3 [OR (95% CI) = 2.15 (1.14: 4.12)]. Of note, bronchiolitis occurrence in patients with a moderate BRST was less than 2 times more likely than in patients with a low BRST [OR (95% CI) = 1.64 (0.73: 3.45)], and this difference was not significant (p = 0.2207). Among the infants experiencing bronchiolitis, almost 68.9% 31/45) did not receive PLV prophylaxis, and no differences were observed in the incidence of bronchiolitis between PLV-treated infants and those who did not receive RSV prophylaxis [OR (95% CI) = 0.98 (0.49: 1.90), p = 0.9548]. TABLE 3 www.frontiersin.org Table 3. Univariate analysis assessing the association between variable bronchiolitis, infants' chara cteristics, and eligibility criteria for RSV prophylaxis with PLV in the study population (n = 296). TABLE 4 www.frontiersin.org Table 4. Univariate analysis assessing the association between variable hospitalization, infants' characteristics, and eligibility criteria for RSV prophylaxis with PLV in infants diagnosed with bronchiolitis (n = 45). 3.4. Ability of the SINLazio score to predict the risk of hospitalization The univariate penalized logistic regression analysis reported in Table 4 shows a statistically significant effect of the SINLazio score on predicting the risk of hospitalization (p = 0.0095), with eight out of ten hospitalized patients having a SINLazio score ≥3. Of note, the chances of being admitted to hospital for bronchiolitis in patients with a SIN score ≥3 were approximately 5.5 times more likely than in patients with a SINLazio score <3 [OR (95% CI) = 5.47 (1.49: 24.92), data not provided]. More than one-third of patients with bronchiolitis (17/45, 37.7%) were hospitalized. These infants required hospitalization for the following reasons: (i) difficulty in feeding (3 out of 17 patients, accounting for 17.6% of inpatients or 6.6% of patients with bronchiolitis); (ii) respiratory difficulties with the need for assistance. Specifically, four patients (23.5% of inpatients and 8.9% of those with bronchiolitis) needed O2-therapy; 10 patients (58.9% of inpatients and 22.2% of bronchiolitis) needed non-invasive ventilatory assistance (High-Flow Nasal Cannula, n-CPAP, or n-IPPV); no patients needed intubation (data not shown). As summarized in Table 4, the 17 infants hospitalized for bronchiolitis would not be undergoing RSV prophylaxis on the basis of the analyzed scores. According to the BRST, > 70% of them (13/17) would not be eligible for PLV treatment. Conversely, most hospitalized patients displayed a SINLazio score ≥3, thus suggesting that these infants could be the most vulnerable patients and may benefit the most from RSV prophylaxis. Among the infants diagnosed with bronchiolitis (Table 3), only 14 out of 45 (31.1%) received PLV prophylaxis; in detail, among the infants hospitalized, namely 17 out of 45, only eight were administered PLV prophylaxis (Table 4). As indicated in Table 4, most of the hospitalized infants [15/17 (88.2%)] have received up to one dose of PLV, thus not availing the benefit of a complete treatment course. The burden of bronchiolitis is relevant for the NICU, thus requiring an increased need for respiratory support. Therefore, minimizing this need may be of relevance. Of note, the risk of requiring a nasal cannula was reported being 91% lower in patients who received PLV than in those not receiving any PLV prophylaxis [OR (95% CI) = 0.09 (0.01: 0.68), p = 0.0174, data not shown]. Among admitted infants, nine had an RSV-positive swab, and all nine did not receive PLV. When evaluating risk factors, the analysis revealed that only two had a moderate BRST. In line with the SINLazio score, six infants had a score ≥3, but they did not receive PLV either because of transfer to another country or because of the refusal of their parents. 4. Discussion It has been well documented that prematurity alone is a significant risk factor for RSV-related hospitalization and severe disease (2, 9, 28, 29), with mid-to-late preterm (infants born between 33 and 35 wGA) being at a significant risk for severe RSV infections. Mounting evidence supports the respiratory vulnerability of moderate-to-late preterm infants that stems from both the early interruption of pulmonary development and the physiologic immaturity of the immune system (2, 30). In addition, infants born preterm have lower levels of maternal antibody that can provide protection against respiratory pathogens (31). Therefore, such population should be targeted by RSV prophylaxis instead of being denied access to PLV treatment, as it is considered low risk in several guidelines (15). As underlined by Priante et al., while it is hard to establish a definite gestational age “threshold” distinguishing between high-risk and low-risk infants, current evidence indicates that preterm infants born at ≤35 wGA are all at risk for severe RSV-related disease than term-born infants, particularly in the early months of life (32). In line with this, previous Italian data support the use of PLV prophylaxis for otherwise healthy preterm (29–35 wGA) infants aged ≤6 months at the beginning of the RSV season (2). Moreover, extending PLV prophylaxis to 29–32 wGA infants appeared to be a cost-effective strategy (33) along with a calculated cost per quality-adjusted life years (QALY) of 14,937.32 € when accomplished in premature infants born between 33 and 35 wGA (34). However, whether PLV prophylaxis could be provided for preterm infants born between 32 and 35 wGA without chronic lung disease and hemodynamically significant congenital heart disease remains a matter of high debate (35). To aid the targeting of prophylaxis for infants born between 33 and 35 wGA at risk for RSV hospitalization, the use of a risk factor model and scoring tool can be helpful in promoting decision-making for clinicians and policymakers. Multifactorial risk scores to identify high-risk moderate/late-preterm infants have been suggested (36, 37) along with a risk scoring tool to predict hospitalization in moderate-late preterm infants (21). In our retrospective analysis, we evaluated whether the adoption of less or more restrictive prophylaxis eligibility criteria (namely, then SINLazio score and BRST) translated into differences in neonatal outcomes (e.g., bronchiolitis and incidence of hospitalization) in a cohort of vulnerable moderate-to-late preterm infants born during two consecutive seasons (2018–2019 and 2019–2020). The SINLazio score allowed us to identify a significant proportion of infants to be considered for prophylaxis, precisely 123 infants with a SINLazio score ≥3. Interestingly, in the same overall population, according to the BRST as indicated in a recent consensus (20), none of the infants should be considered at risk and subsequently eligible for RSV prophylaxis. Therefore, the adoption of a risk scoring tool based on three risk variables [e.g., birth between 3 months before and 2 months after season start date, smokers in the household and/or maternal smoking while pregnant, and siblings (excluding multiples) and/or (planned) daycare attendance] would deny vulnerable infants the opportunity of prophylaxis. Moreover, the observation that those infants with a SINLazio score ≥3 also had a higher risk of bronchiolitis (2.2-fold increase) and of hospitalization (5.5-fold increase) further supports the eligibility of these children for RSV prophylaxis. While a direct comparison between SINLazio and the BRST is not possible as their scoring system is based on similar but not identical parameters, our preliminary data seem to suggest that the adoption of a less restrictive eligibility criteria for PLV prophylaxis may help in identifying infants who could benefit the most from prophylaxis, thereby minimizing the rate of RSV-associated hospitalization and ultimately its long-term clinical sequelae. In our retrospectively analyzed population, approximately 37.7% of infants diagnosed with bronchiolitis (17/45) were hospitalized, with most of them classified as eligible for RSV prophylaxis according to the SINLazio score, but not according to the BRST, for which approximately 70% (13/17) of them would be neither at risk for hospitalization nor eligible for PLV treatment. PLV is a primary prevention strategy for RSV infection worldwide (38). Although the data suggest that PLV treatment is associated with a lower incidence of bronchiolitis and use of hospital-related healthcare resources, in our analysis, the results are not statistically significant due to the small sample size and the observation that most infants with bronchiolitis did not receive the approved PLV treatment regimen (e.g., five injections during the RSV season in an interval of 4 weeks, up to 5 times). Most infants received not more than one dose and a few of them up to 3 doses. This apparent lower RSV protection observed in PLV-treated infants may stem from the observation that, especially between the first and the second injection, the interval of 4 weeks should be strictly adhered to prevent breakthrough infections (an infection occurring despite prophylaxis between the first and the second injection). Accordingly, it has been suggested that the current dose-interval scheme of PLV (administration every 30 days, for 5 months during the epidemic season) may not deliver full protection throughout the entire 1-month interval between doses (39, 40). In addition, a reduced number of PLV doses was reported being unable to protect against severe RSV disease over a typical 5-month RSV season (39–42). Finally, although PLV treatment is recommended to be started on November 1 in our region (23), we could not retrieve the start date for all the PLV-treated infants, and it is likely that not all infants are appropriately receiving PLV treatment according to an optimal timing. It has been well-documented that the timing of the treatment can affect clinical outcomes significantly (43, 44). As a result, starting too early or too late may leave patients vulnerable for a part of the season. Accordingly, delays in administering PLV at the beginning of the season were found to increase the rate of RSV infection–related hospitalization (45). Overall, infants who qualify for PLV treatment should receive the treatment as early as possible and according to a complete 5-dose course protocol. We acknowledge that the present retrospective analysis has several limitations. Particularly, a low number of patients with RSV infection was observed because pharyngeal swabbing is performed exclusively for patients requiring hospitalization (in our case, 17 out of 45 infants). Of these 17 patients hospitalized with bronchiolitis and who underwent a swab analysis for RSV, 9 were positive for the virus of our interest. It was not possible to assess whether hospitalized patients (both those with negative and RSV-positive swabs) were positive for other respiratory viruses, because in the analyzed two seasons, it was not planned to routinely evaluate infection with other respiratory viruses in infants. In addition, this low number of RSV-positive patients stems from the small simple size, because the data were collected only from a single third-level hospital. Finally, the estimated OR with 95% confidence intervals computed for assessing the effects of the demographic–clinical factors on hospitalization and hospital-related complications could be influenced by the small sample size. 5. Conclusion Our preliminary findings support the need for targeting late preterm infants for RSV prophylaxis and, pending further studies and analyses in a larger preterm infant population, call for an appraisal of the current eligibility criteria for PLV treatment to help in the better management of the consequences of RSV infection in vulnerable infants. In addition, our work confirms the importance of acknowledging the eligibility for RSV prophylaxis for moderate-to-late term infants because of their respiratory vulnerability and physiologic immaturity of their immune system that place them at a higher risk of experiencing bronchiolitis. Therefore, adopting less restrictive criteria for eligibility may ensure a comprehensive prophylaxis of the eligible subjects, thus sparing them from avoidable short- and long-term consequences of RSV infection. The evolution in knowledge about the immune response against RSV, as well as the increasing identification of RSV disease burden, has led to an important increase in the number of promising candidates for active and passive immunization. Presently, 3 monoclonal antibodies and 17 active immunization candidates are under development in phase 1 to 3 clinical studies (27). With regard to the first group, Nirsevimab is a monoclonal antibody with a prolonged half-life with approval for clinical use in infants (46, 47). In the coming years, a strategy for the protection of infants and preschoolers could be achieved with a combination of different approaches such as passive immunization, use of monoclonal antibodies, and maternal vaccination during pregnancy. Data availability statement The raw data supporting the conclusions of this article will be made available by the authors without undue reservation. Ethics statement The studies involving human participants were reviewed and approved by Comitato Etico Lazio 2. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. Author contributions VM conceived and designed the study. VM, MB, and NL contributed to data collection. VM, PP, and SP contributed to drafting the article. All authors contributed to the article and approved the submitted version. Funding This work was carried out thanks to an unrestricted educational grant provided by AstraZeneca to EDRA. The authors did not receive any direct or indirect funding. AstraZeneca did not play any role in the design, planning, or execution of the study. The terms of the financial support from AstraZeneca included freedom for the authors to reach their own conclusions and an absolute right to publish the results of this work, irrespective of any conclusions reached. Acknowledgments Statistical analysis was performed by Fabio Gallo. Writing and editing assistance, including preparation of a draft manuscript under the direction and guidance of the authors, incorporation of author feedback, and manuscript submission, was provided by EDRA, with the active support of Chiara Degirolamo, and supported by an unconditioned unrestricted grant from AstraZeneca. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References 1. Li Y, Wang X, Blau DM, Caballero MT, Feikin DR, Gill CJ, et al. 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Infección Respiratoria Infantil por Virus Respiratorio Sincitial Study Group, Pediatric Investigators Collaborative Network on Infections in Canada Study Group. Identifying risk factors for severe respiratory syncytial virus among infants born after 33 through 35 completed weeks of gestation: different methodologies yield consistent findings. Pediatr Infect Dis J. (2004) 23(11 Suppl.):S193–S201. doi: 10.1097/01.inf.0000144664.31888.53 PubMed Abstract | CrossRef Full Text | Google Scholar 37. Simões EA, Carbonell-Estrany X, Fullarton JR, Rossi GA, Barberi I, Lanari M, et al. European risk factors’ model to predict hospitalization of premature infants born 33−35 weeks’ gestational age with respiratory syncytial virus: validation with Italian data. J Matern Fetal Neonatal Med. (2011) 24(1):152–7. doi: 10.3109/14767058.2010.482610 CrossRef Full Text | Google Scholar 38. Esposito S, Abu Raya B, Baraldi E, Flanagan K, Martinon Torres F, Tsolia M, et al. RSV prevention in all infants: which is the most preferable strategy? Front Immunol. (2022) 13:880368. doi: 10.3389/fimmu.2022.880368 PubMed Abstract | CrossRef Full Text | Google Scholar 39. La Via WV, Notario GF, Yu XQ, Sharma S, Noertersheuser PA, Robbie GJ. Three monthly doses of palivizumab are not adequate for 5-month protection: a population pharmacokinetic analysis. Pulm Pharmacol Ther. (2013) 26:666–71. doi: 10.1016/j.pupt.2013.03.007 PubMed Abstract | CrossRef Full Text | Google Scholar 40. Robbie GJ, Zhao L, Mondic KJ, Losonsky G, Roskos LK. Population pharmacokinetics of palivizumab, a humanized anti-respiratory syncytial virus monoclonal antibody, in adults and children. Antimicrob Agents Chemother. (2012) 56:4927–36. doi: 10.1128/AAC.06446-11 PubMed Abstract | CrossRef Full Text | Google Scholar 41. Manzoni P, Paes B, Lanctôt KL, Dall'Agnola A, Mitchell I, Calabrese S, et al. Outcomes of infants receiving palivizumab prophylaxis for respiratory syncytial virus in Canada and Italy: an international, prospective cohort study. Pediatr Infect Dis J. (2017) 36(1):2–8. doi: 10.1097/INF.0000000000001340 PubMed Abstract | CrossRef Full Text | Google Scholar 42. Manzoni P, Sala U, Gomirato G, Coscia A, Fabris C. Optimal timing and dosing intervals of palivizumab in premature neonates: still some work to do. Pediatrics. (2005) 115(5):1439–40. doi: 10.1542/peds.2004-2865 PubMed Abstract | CrossRef Full Text | Google Scholar 43. Artin B, Pitzer VE, Weinberger DM. Assessment and optimization of respiratory syncytial virus prophylaxis in Connecticut, 1996–2013. Sci Rep. (2021) 11:10684. doi: 10.1038/s41598-021-90107-8 PubMed Abstract | CrossRef Full Text | Google Scholar 44. Goddard NL, Cooke MC, Gupta RK, Nguyen-Van-Tam JS. Timing of monoclonal antibody for seasonal RSV prophylaxis in the United Kingdom. Epidemiol Infect. (2007) 135(1):159–62. doi: 10.1017/S0950268806006601 PubMed Abstract | CrossRef Full Text | Google Scholar 45. Kamori A, Morooka Y, Yamamura K, Chong PF, Kuga N, Takahata Y, et al. Effect of delayed palivizumab administration on respiratory syncytial virus infection-related hospitalization. A retrospective, observational study. Medicine. (2021) 100(47):e27952. doi: 10.1097/MD.0000000000027952 PubMed Abstract | CrossRef Full Text | Google Scholar 46. Keam SJ. Nirsevimab: first approval. Drugs. (2023) 83(2):181–7. doi: 10.1007/s40265-022-01829-6 PubMed Abstract | CrossRef Full Text | Google Scholar 47. Álvarez García FJ, Cilleruelo Ortega MJ, Álvarez Aldeán J, Garcés-Sánchez M, Garrote Llanos E, Iofrío de Arce A, et al. Immunisation schedule of the Spanish association of paediatrics: 2023 recommendations. An Pediatr (Engl Ed). (2023) 98(1):58.e1–e10. doi: 10.1016/j.anpede.2022.11.002 CrossRef Full Text | Google Scholar Keywords: respiratory syncytial virus, bronchiolitis, prophylaxis, late preterm, risk factor Citation: Mondì V, Paolillo P, Bedetta M, Lucangeli N and Picone S (2023) Exploring the adoption of less restricted criteria for respiratory syncytial virus prophylaxis in late preterm infants: insights from a retrospective analysis. Front. Pediatr. 11:1154518. doi: 10.3389/fped.2023.1154518 Received: 30 January 2023; Accepted: 16 May 2023; Published: 8 June 2023. Edited by: Mauricio Tomas Caballero, National Scientific and Technical Research Council (CONICET), Argentina Reviewed by: Fernando Ferrero, Hospital Pedro de Elizalde, Argentina Diego Raul Hijano, St. Jude Children’s Research Hospital, United States © 2023 Mondì, Paolillo, Bedetta, Lucangeli and Picone. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. *Correspondence: Vito Mondì vmondi.polcas@eurosanita.it Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. Download

Respiratory Syncytial Virus Prevention through Monoclonal Antibodies: A Cross-Sectional Study on Knowledge, Attitudes, and Practices of Italian Pediatricians

Article

Full-text available

Feb 2023
Pediatr Rep

Respiratory Syncytial Virus (RSV) is a leading cause of morbidity and hospitalization in all infants. Many RSV vaccines and monoclonal antibodies (mAb) are currently under development to protect all infants, but to date preventive options are available only for preterms. In this study, we assessed the knowledge, attitudes, and practices towards RSV and the preventive use of mAb in a sample of Italian Pediatricians. An internet survey was administered through an internet discussion group, with a response rate of 4.4% over the potential respondents (No. 389 out of 8842, mean age 40.1 ± 9.1 years). The association of individual factors, knowledge, and risk perception status with the attitude towards mAb was initially inquired by means of a chi squared test, and all variables associated with mAb with p < 0.05 were included in a multivariable model calculating correspondent adjusted Odds Ratio (aOR) with 95% confidence intervals (95%CI). Of the participants, 41.9% had managed RSV cases in the previous 5 years, 34.4% had diagnosed RSV cases, and 32.6% required a subsequent hospitalization. However, only 14.4% had previously required mAb as immunoprophylaxis for RSV. Knowledge status was substantially inappropriate (actual estimate 54.0% ± 14.2, potential range 0–100), while the majority of participants acknowledged RSV as a substantial health threat for all infants (84.8%). In multivariable analysis, all these factors were characterized as positive effectors for having prescribed mAb (aOR 6.560, 95%CI 2.904–14.822 for higher knowledge score; aOR 6.579, 95%CI 2.919–14.827 for having a hospital background, and a OR 13.440, 95%CI 3.989; 45.287 for living in Italian Major Islands). In other words, reporting less knowledge gaps, having worked in settings with a higher risk of interaction with more severe cases, and being from Italian Major Islands, were identified as positive effectors for a higher reliance on mAb. However, the significant extent of knowledge gaps highlights the importance of appropriate medical education on RSV, its potential health consequences, and the investigational preventive interventions.

UPDATE - 2022 Italian guidelines on the management of bronchiolitis in infants

Article

Full-text available

Feb 2023
Riv Ital Pediatr Ital J Pediatr

Bronchiolitis is an acute respiratory illness that is the leading cause of hospitalization in young children. This document aims to update the consensus document published in 2014 to provide guidance on the current best practices for managing bronchiolitis in infants. The document addresses care in both hospitals and primary care. The diagnosis of bronchiolitis is based on the clinical history and physical examination. The mainstays of management are largely supportive, consisting of fluid management and respiratory support. Evidence suggests no benefit with the use of salbutamol, glucocorticosteroids and antibiotics with potential risk of harm. Because of the lack of effective treatment, the reduction of morbidity must rely on preventive measures. De-implementation of non-evidence-based interventions is a major goal, and educational interventions for clinicians should be carried out to promote high-value care of infants with bronchiolitis. Well-prepared implementation strategies to standardize care and improve the quality of care are needed to promote adherence to guidelines and discourage non-evidence-based attitudes. In parallel, parents' education will help reduce patient pressure and contribute to inappropriate prescriptions. Infants with pre-existing risk factors (i.e., prematurity, bronchopulmonary dysplasia, congenital heart diseases, immunodeficiency, neuromuscular diseases, cystic fibrosis, Down syndrome) present a significant risk of severe bronchiolitis and should be carefully assessed. This revised document, based on international and national scientific evidence, reinforces the current recommendations and integrates the recent advances for optimal care and prevention of acute bronchiolitis.

Identification and evaluation of a novel tribenzamide derivative as an inhibitor targeting the entry of the respiratory syncytial virus

Article

Jan 2023
ANTIVIR RES

Human respiratory syncytial virus (RSV) is the leading cause of severe lower respiratory tract infections in infants, the elderly, and the immunocompromised, yet no licensed vaccine and only limited therapeutic options for prevention and treatment are available, which poses a global health challenge and emphasizes the urgent medical need for novel antiviral agents. In the current study, a novel potent small molecule inhibitor of RSV was identified by performing a screening and structure optimization campaign, wherein a naturally occurring dicaffeoylquinic acid (DCQA) compound served as a chemical starting point. The reported benzamide derivative inhibitor, designated as 2f, was selected for its improved stability and potent antiviral activity from a series of investigated structurally related compounds. 2f was well tolerated by cells and able to inhibit RSV infection with a half maximal inhibitory concentration (IC50) of 35 nM and a favorable selectivity index (SI) of 3742. Although the exact molecular target for 2f is not known, in vitro mechanism of action investigations revealed that the compound inhibits the early stage of infection by interacting with RSV virion and interferes primarily with the attachment and potentially with the virus-cell fusion step. Moreover, intranasal administration of 2f to mice simultaneously or prior to intranasal infection with RSV significantly decreased viral load in the lungs, pointing to the in vivo potential of the compound. Our results suggest that 2f is a viable candidate for further preclinical development and evaluation as an antiviral agent against RSV infections.

PIK-24 Inhibits RSV-Induced Syncytium Formation via Direct Interaction with the p85α Subunit of PI3K

Article

Full-text available

Nov 2022
J VIROL

Phosphoinositide-3 kinase (PI3K) signaling regulates many cellular processes, including cell survival, differentiation, proliferation, cytoskeleton reorganization, and apoptosis. The actin cytoskeleton regulated by PI3K signaling plays an important role in plasma membrane rearrangement. Currently, it is known that respiratory syncytial virus (RSV) infection requires PI3K signaling. However, the regulatory pattern or corresponding molecular mechanism of PI3K signaling on cell-to-cell fusion during syncytium formation remains unclear. This study synthesized a novel PI3K inhibitor PIK-24 designed with PI3K as a target and used it as a molecular probe to investigate the involvement of PI3K signaling in syncytium formation during RSV infection. The results of the antiviral mechanism revealed that syncytium formation required PI3K signaling to activate RHO family GTPases Cdc42, to upregulate the inactive form of cofilin, and to increase the amount of F-actin in cells, thereby causing actin cytoskeleton reorganization and membrane fusion between adjacent cells. PIK-24 treatment significantly abolished the generation of these events by blocking the activation of PI3K signaling. Moreover, PIK-24 had an obvious binding activity with the p85α regulatory subunit of PI3K. The anti-RSV effect similar to PIK-24 was obtained after knockdown of p85α in vitro or knockout of p85α in vivo, suggesting that PIK-24 inhibited RSV infection by targeting PI3K p85α. Most importantly, PIK-24 exerted a potent anti-RSV activity, and its antiviral effect was stronger than that of the classic PI3K inhibitor LY294002, PI-103, and broad-spectrum antiviral drug ribavirin. Thus, PIK-24 has the potential to be developed into a novel anti-RSV agent targeting cellular PI3K signaling. IMPORTANCE PI3K protein has many functions and regulates various cellular processes. As an important regulatory subunit of PI3K, p85α can regulate the activity of PI3K signaling. Therefore, it serves as the key target for virus infection. Indeed, p85α-regulated PI3K signaling facilitates various intracellular plasma membrane rearrangement events by modulating the actin cytoskeleton, which may be critical for RSV-induced syncytium formation. In this study, we show that a novel PI3K inhibitor inhibits RSV-induced PI3K signaling activation and actin cytoskeleton reorganization by targeting the p85α protein, thereby inhibiting syncytium formation and exerting a potent antiviral effect. Respiratory syncytial virus (RSV) is one of the most common respiratory pathogens, causing enormous morbidity, mortality, and economic burden. Currently, no effective antiviral drugs or vaccines exist for RSV infection. This study contributes to understanding the molecular mechanism by which PI3K signaling regulates syncytium formation and provides a leading compound for anti-RSV infection drug development.

Respiratory Syncytial Virus Two-Step Infection Screen Reveals Inhibitors of Early and Late Life Cycle Stages

Article

Full-text available

Nov 2022
ANTIMICROB AGENTS CH

Human respiratory syncytial virus (hRSV) infection is a leading cause of severe respiratory tract infections. Effective, directly acting antivirals against hRSV are not available. We aimed to discover new and chemically diverse candidates to enrich the hRSV drug development pipeline. We used a two-step screen that interrogates compound efficacy after primary infection and a consecutive virus passaging. We resynthesized selected hit molecules and profiled their activities with hRSV lentiviral pseudotype cell entry, replicon, and time-of-addition assays. The breadth of antiviral activity was tested against recent RSV clinical strains and human coronavirus (hCoV-229E), and in pseudotype-based entry assays with non-RSV viruses. Screening 6,048 molecules, we identified 23 primary candidates, of which 13 preferentially scored in the first and 10 in the second rounds of infection, respectively. Two of these molecules inhibited hRSV cell entry and selected for F protein resistance within the fusion peptide. One molecule inhibited transcription/replication in hRSV replicon assays, did not select for phenotypic hRSV resistance and was active against non-hRSV viruses, including hCoV-229E. One compound, identified in the second round of infection, did not measurably inhibit hRSV cell entry or replication/transcription. It selected for two coding mutations in the G protein and was highly active in differentiated BCi-NS1.1 lung cells. In conclusion, we identified four new hRSV inhibitor candidates with different modes of action. Our findings build an interesting platform for medicinal chemistry-guided derivatization approaches followed by deeper phenotypical characterization in vitro and in vivo with the aim of developing highly potent hRSV drugs.

LB-1Treatment with Oral ALS-008176, a Nucleoside Analog, Rapidly Reduces RSV Viral Load and Clinical Disease Severity in a Healthy Volunteer Challenge Study

Article

Full-text available

Dec 2014

Nebulized hypertonic saline solution for acute bronchiolitis in infants

Article

Full-text available

Jan 2009

Background: Airway edema and mucus plugging are the predominant pathological features in infants with acute viral bronchiolitis. Nebulized hypertonic saline solution may reduce these pathological changes and decrease airway obstruction. Objectives: To assess the effects of nebulized hypertonic saline solution in infants with acute viral bronchiolitis. Search strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, issue 4), which contains the Cochrane Acute Respiratory Infections Group Specialized Register; OLDMEDLINE (1951 to 1965); MEDLINE (1966 to November 2007); EMBASE (1974 to November 2007); and LILACS (November 2007). Selection criteria: Randomised controlled trials (RCTs) and quasi-RCTs using nebulized hypertonic saline alone or in conjunction with bronchodilators as an active intervention in infants up to 24 months of age with acute bronchiolitis. Data collection and analysis: Two review authors (ZL, MRA) independently performed data extraction and study quality assessment. We pooled the data from individual trials using the Cochrane statistical package Review Manager (RevMan). Main results: We included four trials involving 254 infants with acute viral bronchiolitis (189 inpatients and 65 outpatients) in this review. Patients treated with nebulized 3% saline had a significantly shorter mean length of hospital stay compared to those treated with nebulized 0.9% saline (mean difference (MD) -0.94 days, 95% CI -1.48 to -0.40, P = 0.0006). The 3% saline group also had a significantly lower post-inhalation clinical score than the 0.9% saline group in the first three days of treatment (day 1: MD -0.75, 95% CI -1.38 to -0.12, P = 0.02; day 2: MD -1.18, 95% CI -1.97 to -0.39, P = 0.003; day 3: MD -1.28, 95% CI -2.57 to 0.00, P = 0.05). The effect of nebulized hypertonic saline in improving clinical score was greater among outpatients than inpatients. No adverse events related to 3% saline inhalation were reported. Authors' conclusions: Current evidence suggests nebulized 3% saline may significantly reduce the length of hospital stay and improve the clinical severity score in infants with acute viral bronchiolitis. Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Frequent Asymptomatic Respiratory Syncytial Virus Infections During an Epidemic in a Rural Kenyan Household Cohort

Article

Full-text available

May 2015
J INFECT DIS

Background: The characteristics, determinants, and potential contribution to transmission of asymptomatic cases of respiratory syncytial virus (RSV) infection have not been well described. Methods: A cohort of 47 households (493 individuals) in coastal Kenya was recruited and followed for a 26-week period spanning a complete RSV season. Nasopharyngeal swab specimens were requested weekly, during the first 4 weeks, and twice weekly thereafter from all household members, regardless of illness status. The samples were screened for a range of respiratory viruses by multiplex real-time polymerase chain reaction. Results: Tests on 16 928 samples yielded 205 RSV infection episodes in 179 individuals (37.1%) from 40 different households. Eighty-six episodes (42.0%) were asymptomatic. Factors independently associated with an increased risk of asymptomatic RSV infection episodes were higher age, shorter duration of infection, bigger household size, lower peak viral load, absence of concurrent RSV infections within the household, infection by RSV group B, and no prior human rhinovirus infections. The propensity of RSV spread in households was dependent on symptom status and amount (duration and load) of virus shed. Conclusions: While asymptomatic RSV was less likely to spread, the high frequency of symptomless RSV infection episodes highlights a potentially important role of asymptomatic infections in the community transmission of RSV.

Failure of high flow nasal cannula (HFNC) and delayed intubation: a new harmful sequence?"

Article

Full-text available

May 2015

Dear Editor,Presently, there is general agreement regarding the benefits of high-flow nasal cannula (HFNC) in certain forms of acute hypoxemic respiratory failure (AHRF); however, which clinical circumstances constitute HFNC failure and whether HFNC use unnecessarily delays endotracheal intubation (ETI) are controversial [1]. Kang et al. [3] analysed the impact of the timing of ETI relative to the determination of HFNC failure. We feel that this estimation warrants consideration.First, from a methodological standpoint, Kang et al. [3] enrolled patients with multiple reasons for AHRF. Defining two cohorts on the basis of early or late ETI but having those cohorts contain different numbers of patients with each etiologic category of AHRF makes it difficult to determine the independent contribution of timing of ETI to the outcomes of interest. Indeed, we might expect patients with specific conditions, like haematological malignancies, to fare worse in the setting of AHRF, regardless of th ...

Hypertonic (3%) Saline Vs 0.9% Saline Nebulization for Acute Viral Bronchiolitis: A Randomized Controlled Trial

Article

Full-text available

Aug 2013

Objective: To compare the length of hospital stay (primary) and improvement in clinical severity scores (secondary) among children with bronchiolitis nebulized with 3 % hypertonic saline or 0.9% saline. Design: Randomized double blind controlled trial. Settings: Tertiary care teaching hospital. Patients: Hospitalized children (1-24 months) with acute bronchiolitis of moderate severity. Intervention: Nebulization of 4 ml of 3% hypertonic saline or 4 mL of 0.9% saline, along with 2.5 mg salbutamol, at 4-hourly intervals till the patient was ready for discharge. Results: Baseline characteristics were similar in two groups. Median clinical severity score at admission was 6 (IQR-1) in both the groups. Clinical severity scores monitored afterwards 12-hourly till discharge (132 h) did not show statistically significant differences in 3% and 0.9% saline groups. Mean length of hospital stay (time to reach predefined clinical severity score<3) was 63.93 ± 22.43 h in 3% saline group and 63.51 ± 21.27 h in 0.9% saline group (P=0.878). No adverse events were reported by the parents, caregivers or treating medical attendants in both groups. Conclusion: Nebulized 3 % saline is not superior to 0.9% saline in infants with clinically diagnosed acute bronchiolitis.

Global, regional, and national age–sex specific all-cause and cause-specific mortality for 240 causes of death, 1990–2013: A systematic analysis for the Global Burden of Disease Study 2013

Article

Full-text available

Jan 2015

Background: Up-to-date evidence on levels and trends for age-sex-specific all-cause and cause-specific mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries. Methods: We estimated age-sex-specific all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specific causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions. Findings: Global life expectancy for both sexes increased from 65·3 years (UI 65·0–65·6) in 1990, to 71·5 years (UI 71·0–71·9) in 2013, while the number of deaths increased from 47·5 million (UI 46·8–48·2) to 54·9 million (UI 53·6–56·3) over the same interval. Global progress masked variation by age and sex: for children, average absolute differences between countries decreased but relative differences increased. For women aged 25–39 years and older than 75 years and for men aged 20–49 years and 65 years and older, both absolute and relative differences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10·7%, from 4·3 million deaths in 1990 to 4·8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100 000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions. Interpretation: For most countries, the general pattern of reductions in age-sex specific mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade.

SABRE: A multicentre randomised control trial of nebulised hypertonic saline in infants hospitalised with acute bronchiolitis

Article

Full-text available

Dec 2014

Aim Acute bronchiolitis is the commonest cause for hospitalisation in infancy. Supportive care remains the cornerstone of current management and no other therapy has been shown to influence the course of the disease. It has been suggested that adding nebulised hypertonic saline to usual care may shorten the duration of hospitalisation. To determine whether hypertonic saline does have beneficial effects we undertook an open, multi-centre parallel-group, pragmatic RCT in ten UK hospitals. Methods Infants admitted to hospital with a clinical diagnosis of acute bronchiolitis and requiring oxygen therapy were randomised to receive usual care alone or nebulised 3% hypertonic saline (HS) administered 6-hourly. Randomisation was within 4 h of admission. The primary outcome was time to being assessed as ‘fit’ for discharge with secondary outcomes including time to discharge, incidence of adverse events together with follow up to 28 days assessing patient centred health related outcomes. Results A total of 317 infants were recruited to the study. 158 infants were randomised to HS (141 analysed) and 159 to standard care (149 analysed). There was no difference between the two arms in time to being declared fit for discharge (hazard ratio: 0−95, 95% CI: 0.75−1.20) nor to actual discharge (hazard ratio: 0.97, 95% CI: 0.76−1.23). There was no difference in adverse events. One infant in the HS group developed bradycardia with desaturation. Conclusion This study does not support the use of nebulised HS in the treatment of acute bronchiolitis over usual care with minimal handlings. ClinicalTrials.gov registration number NCT01469845.

Treatment with Oral ALS-008176, a Nucleoside Analog, Rapidly Reduces RSV Viral Load and Clinical Disease Severity in a Healthy Volunteer Challenge Study

Conference Paper

Full-text available

Oct 2014

Background: RSV infection causes substantial morbidity and mortality including severe and often fatal cases in immunocompromized patients. However, no effective therapeutic antiviral exists. We conducted a double-blind, placebo (PLB)-controlled Phase 2a study to evaluate ALS‑008176 in adult volunteers infected with a clinical strain of RSV. Methods: Subjects were healthy volunteers, 18-45 years, with pre-existing RSV-A specific antibody titres (lowest 25th percentile of the population). After being inoculated with RSV-A Memphis 37b virus on Study Day 0 (D0), subjects were monitored for RSV infection in nasal wash every 12 hours using a qualitative RT-PCR assay. Twelve hours after infection was detected by PCR, or 6 days after inoculation (D6), whichever was first, subjects were randomized to ALS-008176 or PLB and dosed q12 hrs X 5 days. Nasal wash viral load (VL; qPCR), RSV symptom scores, and mucus weight were evaluated multiple times daily through D12, and on D16 and D28. Safety was evaluated through D28. The primary endpoint was the area under the curve (AUC) of RSV VL from prior to 1st dose through D12. Efficacy analyses were conducted on infected subjects (intent to treat-infected (ITT-I) population). Results: 62 subjects were randomized to PLB or 1 of 3 ALS-008176 dosing regimens (750 mg loading dose (LD)/500 mg maintenance doses (MD), 750 mg LD/150 mg MD, 375 mg Q12). 35 subjects met the criterion for infection (ITT-I population). VL AUC was reduced in all ALS-008176 dosing regimens vs. PLB (p all <0.001), and viral clearance was accelerated (p all <0.05). Symptom Score and Mucus Weight AUC were reduced for all treatment groups vs. PLB. No subject exhibited VL rebound. No clinically significant safety laboratory abnormalities were noted. All adverse events were mild or moderate and generally balanced between active and PLB groups; none were serious or led to discontinuation. Conclusions: ALS-008176 appeared safe, and demonstrated potent antiviral activity resulting in rapid multi-log10 decline and clearance of RSV RNA, with concomitant improvements in clinical RSV disease severity. ALS 8176 should be evaluated in clinical populations with severe and life-threatening RSV infections.

Clinical Practice Guideline: The Diagnosis, Management, and Prevention of Bronchiolitis

Article

Full-text available

Oct 2014

This guideline is a revision of the clinical practice guideline, "Diagnosis and Management of Bronchiolitis," published by the American Academy of Pediatrics in 2006. The guideline applies to children from 1 through 23 months of age. Other exclusions are noted. Each key action statement indicates level of evidence, benefit-harm relationship, and level of recommendation. Key action statements are as follows:

Oral GS-5806 Activity in a Respiratory Syncytial Virus Challenge Study

Article

Full-text available

Aug 2014

Background: Respiratory syncytial virus (RSV) is a common cause of infant hospitalizations and is increasingly recognized as a cause of considerable morbidity and mortality. No accepted antiviral treatment exists. Methods: We conducted a double-blind, placebo-controlled study of GS-5806, an oral RSV-entry inhibitor, in healthy adults who received a clinical challenge strain of RSV intranasally. Participants were monitored for 12 days. At the time of a positive test for RSV infection or 5 days after inoculation, whichever occurred first, participants were randomly assigned to receive GS-5806 or placebo in one of seven sequential cohorts. Cohorts 1 to 4 received a first dose of 50 mg of GS-5806 and then 25 mg daily for the next 4 days, cohort 5 received a first dose of 50 mg and then 25 mg daily for the next 2 days, cohort 6 received one 100-mg dose, and cohort 7 received a first dose of 10 mg and then 5 mg daily for the next 4 days. Dose selection for cohorts 5, 6, and 7 occurred after an interim analysis of data for cohorts 1 to 4. The primary end point was the area under the curve (AUC) for the viral load, which was assessed after administration of the first dose through the 12th day after inoculation. Secondary end points were mucus weight and symptom scores. Results: Among the 54 participants in cohorts 1 to 4 who were infected with RSV, active treatment was associated with a lower viral load (adjusted mean, 250.7 vs. 757.7 log10 plaque-forming-unit equivalents [PFUe] × hours per milliliter; P<0.001), lower total mucus weight (mean, 6.9 g vs. 15.1 g; P=0.03), and a lower AUC for the change from baseline in symptom scores (adjusted mean, -20.2 vs. 204.9 × hours; P=0.005). The results were similar in cohorts 5, 6, and 7. Adverse events, including low neutrophil counts and increased levels of alanine aminotransferase, were more common among participants receiving GS-5806. Conclusions: Treatment with GS-5806 reduced the viral load and the severity of clinical disease in a challenge study of healthy adults. (Funded by Gilead Sciences; ClinicalTrials.gov number, NCT01756482.).

Modification of the RSV F Protein in Virus-like Particles Impacts Generation of B Cell Memory.

Article

Full-text available

Aug 2014
J VIROL

Unlabelled: Immunization with virus-like particles (VLPs) containing the Newcastle disease virus (NDV) core proteins, NP and M, and two chimera proteins (F/F and H/G) containing the respiratory syncytial virus (RSV) F- and G-protein ectodomains fused to the transmembrane and cytoplasmic domains of NDV F and HN proteins, respectively, stimulated durable RSV-neutralizing antibodies, F-protein-specific long-lived, bone marrow-associated plasma cells (LLPCs), and B cell memory, in striking contrast to RSV infection, which did not (M. R. Schmidt, L. W. McGinnes, S. A. Kenward, K. N. Willems, R. T. Woodland, and T. G. Morrison, J. Virol. 86:11654-11662, 2012). Here we report the characterization of a VLP with an RSV F-protein ectodomain fused to the NDV F-protein heptad repeat 2 (HR2), transmembrane, and cytoplasmic domain sequences, creating a chimera with two tandem HR2 domains, one from the RSV F protein and the other from the NDV F-protein ectodomain (F/HR2F). The F/HR2F chimera protein was efficiently assembled into VLPs along with the H/G chimera protein. This VLP (VLP-H/G+F/HR2F) stimulated anti-F-protein and anti-G-protein IgG, durable RSV-neutralizing antibodies, and anti-RSV F-protein-secreting LLPCs. However, the subtypes of anti-F-protein IgG induced were different from those elicited by VLPs containing the F/F chimera (VLP-H/G+F/F). Most importantly, VLP-H/G+F/HR2F did not induce RSV F-protein-specific B cell memory, as shown by the adoptive transfer of B cells from immunized animals to immunodeficient animals. The VLP did, however, induce B cell memory specific to the RSV G protein. Thus, the form of the F protein has a direct role in inducing anti-F-protein B cell memory. Importance: The development of vaccines for respiratory syncytial virus (RSV) is hampered by a lack of a clear understanding of the requirements for eliciting protective as well as durable human immune responses to virus antigens. The results of this study indicate that the form of the RSV F protein has a direct and significant impact on the type of anti-F-protein IgG antibodies induced and the generation of F-protein-specific memory. Identification of the conformation of the RSV F protein that most effectively stimulates not only LLPCs and but also memory B cells will be important in the future development of RSV vaccines.

Nebulized Hypertonic Saline for Bronchiolitis in the Emergency Department A Randomized Clinical Trial

Article

Full-text available

May 2014

Importance Acute bronchiolitis is the most frequent lower respiratory tract infection in infants, yet there are no effective therapies available. Current evidence is unclear about the role of hypertonic saline (HS) for the acute treatment of bronchiolitis.Objective To determine whether nebulized 3% HS compared with normal saline (NS) improves respiratory distress in infants with bronchiolitis not responding to standard treatments in the emergency department.Design, Setting, and Participants A randomized clinical trial with blinding of investigators, health care providers, and parents was conducted at a single urban pediatric ED. The participants included children aged 2 to less than 24 months with their first episode of bronchiolitis and a Respiratory Distress Assessment Instrument score of 4 to 15 after nasal suctioning and a trial of nebulized albuterol. Interventions Patients were randomized to receive either nebulized 3% HS (HS group) or NS (NS group).Main Outcomes and Measures The primary outcome was change in respiratory distress at 1 hour after the intervention, as measured by the Respiratory Assessment Change Score (a decrease indicates improvement). Secondary outcomes included vital signs, oxygen saturation, hospitalization, physician clinical impression, parental assessment, and adverse events.Results The 31 patients enrolled in each treatment arm had similar baseline demographic and clinical characteristics. At 1 hour after the intervention, the HS group demonstrated significantly less improvement in the median Respiratory Assessment Change Score compared with the NS group (HS, −1 [interquartile range, −5 to 1] vs NS, −5 [interquartile range, −6 to −2]; P = .01). There were no significant differences in heart rate, oxygen saturation, hospitalization rate, or other outcomes. There were no adverse events.Conclusions and Relevance Infants with bronchiolitis and persistent respiratory distress after standard treatment in the emergency department had less improvement after receiving 3% HS compared with those who received NS. Based on these results and the existing evidence, administration of a single dose of 3% HS does not appear to be indicated to treat bronchiolitis in the acute care setting.Trial Registration clinicaltrials.gov Identifier: NCT01247064

Duration of symptoms of respiratory tract infections in children: Systematic review

Article

Full-text available

Dec 2013
Br Med J

To determine the expected duration of symptoms of common respiratory tract infections in children in primary and emergency care. Systematic review of existing literature to determine durations of symptoms of earache, sore throat, cough (including acute cough, bronchiolitis, and croup), and common cold in children. PubMed, DARE, and CINAHL (all to July 2012). Randomised controlled trials or observational studies of children with acute respiratory tract infections in primary care or emergency settings in high income countries who received either a control treatment or a placebo or over-the-counter treatment. Study quality was assessed with the Cochrane risk of bias framework for randomised controlled trials, and the critical appraisal skills programme framework for observational studies. Individual study data and, when possible, pooled daily mean proportions and 95% confidence intervals for symptom duration. Symptom duration (in days) at which each symptom had resolved in 50% and 90% of children. Of 22,182 identified references, 23 trials and 25 observational studies met inclusion criteria. Study populations varied in age and duration of symptoms before study onset. In 90% of children, earache was resolved by seven to eight days, sore throat between two and seven days, croup by two days, bronchiolitis by 21 days, acute cough by 25 days, common cold by 15 days, and non-specific respiratory tract infections symptoms by 16 days. The durations of earache and common colds are considerably longer than current guidance given to parents in the United Kingdom and the United States; for other symptoms such as sore throat, acute cough, bronchiolitis, and croup the current guidance is consistent with our findings. Updating current guidelines with new evidence will help support parents and clinicians in evidence based decision making for children with respiratory tract infections.

Respiratory Syncytial Virus and Recurrent Wheeze in Healthy Preterm Infants

Article

Full-text available

May 2013
NEW ENGL J MED

Respiratory syncytial virus (RSV) infection is associated with subsequent recurrent wheeze. Observational studies cannot determine whether RSV infection is the cause of recurrent wheeze or the first indication of preexistent pulmonary vulnerability in preterm infants. The monoclonal antibody palivizumab has shown efficacy in preventing severe RSV infection in high-risk infants. In the double-blind, placebo-controlled MAKI trial, we randomly assigned 429 otherwise healthy preterm infants born at a gestational age of 33 to 35 weeks to receive either monthly palivizumab injections (214 infants) or placebo (215 infants) during the RSV season. The prespecified primary outcome was the total number of parent-reported wheezing days in the first year of life. Nasopharyngeal swabs were taken during respiratory episodes for viral analysis. Palivizumab treatment resulted in a relative reduction of 61% (95% confidence interval, 56 to 65) in the total number of wheezing days during the first year of life (930 of 53,075 days in the RSV-prevention group [1.8%] vs. 2309 of 51,726 days [4.5%] in the placebo group). During this time, the proportion of infants with recurrent wheeze was 10 percentage points lower in patients treated with palivizumab (11% vs. 21%, P=0.01). In otherwise healthy preterm infants, palivizumab treatment resulted in a significant reduction in wheezing days during the first year of life, even after the end of treatment. These findings implicate RSV infection as an important mechanism of recurrent wheeze during the first year of life in such infants. (Funded by Abbott Laboratories and by the Netherlands Organization for Health Research and Development; MAKI Controlled Clinical Trials number, ISRCTN73641710.).

The pharmacokinetics of conventional and bioenhanced tablet formulations of danirixin (GSK1325756) following oral administration in healthy, elderly, human volunteers

Article

Full-text available

Feb 2014

Danirixin (GSK1325756) is a small, high-affinity, selective and reversible CXCR2 antagonist in development for treatment of chronic obstructive pulmonary disease. The objective of the study was to evaluate the relative bioavailability, including the inter-subject variability, of a conventional immediate-release (IR) formulation and two prototype bioenhanced formulations of danirixin during gastric acid suppression in a healthy, elderly population. A single-centre, crossover study in healthy male and female volunteers aged 65–80 years was conducted. Subjects were randomised to receive danirixin 50 mg IR in the fed and fasted states and danirixin 50 mg Bioenhanced Formulation 1 and 2 in the fasted state. All subjects also received omeprazole 20 mg each morning beginning 4 days prior to the first treatment period and continuing through danirixin dosing in the final treatment period. Twenty subjects were randomised and completed the study. Bioenhanced Formulation 2 in the fasted state demonstrated the highest adjusted geometric means for AUC(0–t), AUC(0–inf), AUC(0–24) and C max. Danirixin IR demonstrated adjusted means that were higher in the fed state compared with the fasted state. For all formulations tested, there was substantial inter-subject variability (CVb >100 % for all formulations). The overall incidences of adverse events (AEs) were 10 % for danirixin IR (both in the fed and fasted states) and 15–20 % for the bioenhanced formulations. The majority of AEs were mild in intensity. There were no serious AEs. Concomitant use of omeprazole resulted in large inter-subject variability in the exposure to danirixin. Bioenhanced formulation strategies could not overcome the effect of omeprazole on exposure and variability between subjects.

Epidemiology of Respiratory Syncytial Virus-Associated Acute Lower Respiratory Tract Infection Hospitalizations Among HIV-Infected and HIV-Uninfected South African Children, 2010-2011

Article

Full-text available

Nov 2013

Background: There are limited data on respiratory syncytial virus (RSV) infection among children in settings with a high prevalence of human immunodeficiency virus (HIV). We studied the epidemiology of RSV-associated acute lower respiratory tract infection (ALRTI) hospitalizations among HIV-infected and HIV-uninfected children in South Africa. Methods: Children aged <5 years admitted to sentinel surveillance hospitals with physician-diagnosed neonatal sepsis or ALRTI were enrolled. Nasopharyngeal aspirates were tested by multiplex real-time polymerase chain reaction assays for RSV and other viruses. Associations between possible risk factors and severe outcomes for RSV infection among HIV-infected and uninfected children were examined. The relative risk of hospitalization in HIV-infected and HIV-uninfected children was calculated in 1 site with population denominators. Results: Of 4489 participants, 4293 (96%) were tested for RSV, of whom 1157 (27%) tested positive. With adjustment for age, HIV-infected children had a 3-5-fold increased risk of hospitalization with RSV-associated ALRTI (2010 relative risk, 5.6; [95% confidence interval (CI), 4.5-6.4]; 2011 relative risk, 3.1 [95% CI, 2.6-3.6]). On multivariable analysis, HIV-infected children with RSV-associated ALRTI had higher odds of death (adjusted odds ratio. 31.1; 95% CI, 5.4-179.8) and hospitalization for >5 days (adjusted odds ratio, 4.0; 95% CI, 1.5-10.6) than HIV-uninfected children. Conclusion: HIV-infected children have a higher risk of hospitalization with RSV-associated ALRTI and a poorer outcome than HIV-uninfected children. These children should be targeted for interventions aimed at preventing severe RSV disease.

The Source Of Respiratory Syncytial Virus Infection In Infants: A Household Cohort Study In Rural Kenya.

Article

Full-text available

Dec 2013
J INFECT DIS

Background. Respiratory syncytial virus (RSV) vaccine development for direct protection of young infants faces substantial obstacles. Assessing the potential of indirect protection using different strategies, such as targeting older children or mothers, requires knowledge of the source of infection to the infants. Methods. We undertook a prospective study in rural Kenya. Households with a child born after the preceding RSV epidemic and ≥1 elder sibling were recruited. Nasopharyngeal swab samples were collected every 3–4 days irrespective of symptoms from all household members throughout the RSV season of 2009–2010 and tested for RSV using molecular techniques. Results. From 451 participants in 44 households a total of 15 396 nasopharyngeal swab samples were samples were collected, representing 86% of planned sampling. RSV was detected in 37 households (84%) and 173 participants (38%) and 28 study infants (64%). The infants acquired infection from within (15 infants; 54%) or outside (9 infants; 32%) the household; in 4 households the source of infant infection was inconclusive. Older children were index case patients for 11 (73%) of the within-household infant infections, and 10 of these 11 children were attending school. Conclusion. We demonstrate that school-going siblings frequently introduce RSV into households, leading to infection in infants.

Motavizumab Treatment of Infants Hospitalized With Respiratory Syncytial Virus Infection Does Not Decrease Viral Load or Severity of Illness

Article

Full-text available

Dec 2013
PEDIATR INFECT DIS J

This study was conducted to determine whether treatment with motavizumab, an anti-RSV monoclonal antibody, would decrease viral load and improve clinical outcomes in previously healthy term infants hospitalized with RSV lower respiratory tract infection (LRTI). Infants hospitalized with LRTI and a positive RSV test performed locally were randomized to receive 1 intravenous dose of motavizumab (30 or 100 mg/kg) or placebo. Nasal wash samples were tested by real-time RT-PCR at a central laboratory to determine viral load. Clinical data were collected during RSV hospitalization and at 12-month follow-up. Of 118 infants, 112 were confirmed RSV-positive by RT-PCR. In each study group, median (range) RSV load (log10 copies/mL) decreased at a similar rate from baseline to study day 7 (motavizumab 30 mg/kg: 8.35 [2.5-9.5] to 5.03 [2.5-6.8]; motavizumab 100 mg/kg: 8.22 [5.5-9.7] to 4.25 [2.5-8.0]; placebo: 8.02 [6.7-9.8] to 5.17 [2.5-7.3]). Median (range) duration of hospitalization was 3.05 (0.8-16.0), 2.99 (1.0-25.0), and 2.88 (0.8-11.7) days for the motavizumab 30-mg/kg, motavizumab 100-mg/ kg, and placebo groups, respectively. Six (8%) motavizumab and 0 placebo recipients were admitted to the ICU; 4 required mechanical ventilation. The incidence of wheezing episodes during the 12-month follow-up was comparable for all 3 groups. Motavizumab had no appreciable effect on RSV viral load measured in the upper respiratory tract of children hospitalized for RSV LRTI. No differences were observed for duration of hospitalization, severity of illness measures, or wheezing episodes during 12-month follow-up in children treated with motavizumab or placebo.

Safety and Immunogenicity of a Live Attenuated RSV Vaccine in Healthy RSV-Seronegative Children 5 to 24 Months of Age

Article

Full-text available

Oct 2013
PLOS ONE

Unlabelled: Despite substantial morbidity associated with respiratory syncytial virus (RSV) infection, there is no licensed vaccine. MEDI-559 is a live attenuated intranasal vaccine candidate being developed for prevention of lower respiratory illness due to RSV in young children. This randomized, placebo-controlled study evaluated safety of MEDI-559 in healthy, RSV-seronegative children. MEDI-559 or placebo was administered on 3 occasions, 2 months apart. Primary safety was based on solicited symptoms (SSs) and adverse events (AEs) collected for 28 days after each dose. Nasal wash samples were collected 3 times after each dose (days 7-10, 12-18, 28-34) and at sick visits. Serum was collected for measuring antibody immune responses to RSV prior to first vaccination and 28 days post final dose. Long-term safety was monitored for 365 days from first dose. SSs were mild and frequent (MEDI-559 84%; placebo 91%); most common SSs were runny/stuffy nose, cough, and irritability/fussiness. AEs occurred in 67% MEDI-559 and 57% placebo recipients: most common AE was upper respiratory tract infection (MEDI-559 35%; placebo 23%). Higher incidence of medically attended lower respiratory illness within 28 days after dosing occurred in the MEDI-559 arm compared to placebo (none associated with vaccine virus shedding). There was no evidence of enhanced RSV disease. Vaccine virus was detected only in MEDI-559 recipients; shedding occurred in 56%subjects, primarily post dose 1. A functional immune response was observed in 59% and 9% MEDI-559 and placebo recipients, respectively, by an RSV microneutralization assay. Vaccine take, assessed by proportion that shed vaccine-type virus or had a seroresponse against RSV, was seen in 95% MEDI-559 subjects. MEDI-559 is therefore biologically active and immunogenic in this seronegative pediatric population. Although the frequency of SSs and AEs was not considered clinically significant, the increase in medically attended lower respiratory illnesses in the vaccine group warrants expanded safety studies. Trial registration: ClinicalTrials.gov NCT00767416.

A Novel Investigational Fc-Modified Humanized Monoclonal Antibody, Motavizumab-YTE, Has an Extended Half-Life in Healthy Adults

Article

Full-text available

Nov 2013
ANTIMICROB AGENTS CH

The study objective was to evaluate the pharmacokinetics (PK), antidrug antibody (ADA), and safety of motavizumab-YTE (motavizumab with amino acid substitutions M252Y/S254T/T256E [YTE]), an Fc-modified anti-respiratory syncytial virus (RSV) monoclonal antibody. Healthy adults (n = 31) were randomized to receive a single intravenous (i.v.) dose of motavizumab-YTE or motavizumab (0.3, 3, 15, or 30 mg/kg) and followed for 240 days. Clearance of motavizumab-YTE was significantly lower (71% to 86%) and the half-life (t1/2) was 2- to 4-fold longer than with motavizumab. However, similar peak concentrations and volume-of-distribution values, indicative of similar distribution properties, were seen at all dose levels. The sustained serum concentrations of motavizumab-YTE were fully functional, as shown by RSV neutralizing activity that persisted for 240 days with motavizumab-YTE versus 90 days postdose for motavizumab. Safety and incidence of ADA were comparable between groups. In this first study of an Fc-modified monoclonal antibody in humans, motavizumab-YTE was well tolerated and exhibited an extended half-life of up to 100 days. (This study has been registered at ClinicalTrials.gov under registration no. NCT00578682.)

Lower respiratory tract infection caused by Respiratory Syncytial Virus: current management and new therapeutics.

Abstract

No full-text available