Daily Respiratory Research Analysis
Analyzed 87 papers and selected 3 impactful papers.
Summary
Analyzed 87 papers and selected 3 impactful articles.
Selected Articles
1. Clesrovimab in Infants at Increased Risk For Severe Disease During 2 RSV Seasons: A Randomized Clinical Trial.
In a multicountry, phase 3 randomized trial of high-risk infants, clesrovimab (105 mg) had adverse event rates comparable to palivizumab during the first RSV season, and open-label clesrovimab 210 mg was well tolerated in the second season. RSV-associated medically attended lower respiratory infection rates were similar between clesrovimab and palivizumab in season 1, and 7.3% through day 180 after 210 mg in season 2.
Impact: This trial provides robust, randomized evidence supporting clesrovimab safety across two consecutive RSV seasons in high-risk infants, directly informing prophylaxis strategies beyond the first season.
Clinical Implications: Clinicians can consider clesrovimab as an alternative to palivizumab in season 1 and for continued protection in season 2 among infants who remain at high risk, with comparable safety and practical single-dose administration per season.
Key Findings
- Season 1 adverse event rates were comparable between clesrovimab (105 mg) and palivizumab.
- Open-label clesrovimab 210 mg in season 2 was well tolerated.
- RSV-associated MALRI incidence was similar between clesrovimab and palivizumab through day 150 in season 1; season 2 MALRI incidence after 210 mg was 7.3% through day 180.
- Hospital days and severe events were low and similar across groups; safety profile aligned with prior studies.
Methodological Strengths
- Randomized, multicenter, active-controlled phase 3 design across 27 countries
- Stratified randomization with prespecified safety endpoints and season 2 follow-on
Limitations
- Partial masking and primary focus on safety rather than efficacy endpoints
- Season 2 was open-label without a randomized comparator
Future Directions: Head-to-head efficacy trials powered for clinical outcomes (hospitalization, ICU use) and cost-effectiveness analyses across seasons will clarify optimal deployment and access strategies.
IMPORTANCE: Clesrovimab is a long-acting monoclonal antibody approved for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in neonates and infants who are born during or entering their first RSV season; data concerning clesrovimab from a second RSV season among children who remain at risk for severe disease are needed. OBJECTIVE: To evaluate the safety and tolerability of clesrovimab (105 mg) vs palivizumab in RSV season 1 in infants at increased risk for severe RSV disease. Key secondary objectives include describing the safety of 210 mg of clesrovimab in RSV season 2 in children who remain at increased risk for severe RSV disease, clesrovimab pharmacokinetics, and the incidence of RSV-associated disease. DESIGN, SETTING, AND PARTICIPANTS: SMART (MK-1654-007) was a randomized, partially masked, palivizumab-controlled, phase 3 clinical trial, conducted at 110 sites in 27 countries and territories between November 30, 2021, and November 20, 2025. The population constituted palivizumab-eligible infants, including those with prematurity, chronic lung disease of prematurity, or hemodynamically significant congenital heart disease. INTERVENTIONS: Participants, randomized 1:1 and stratified by region and condition, received clesrovimab (105 mg) on day 1 followed by placebo on day 28 or monthly palivizumab (15 mg/kg) up to 5 doses (1 dose per month). Eligible infants received open-label clesrovimab (210 mg) before their second RSV season. MAIN OUTCOMES AND MEASURES: The primary outcome was the observed proportions of participants experiencing adverse events (AEs) after clesrovimab or palivizumab in season 1.
2. Particles of echovirus 18 open to release their genomes in vivo.
Using in situ cryo-electron tomography, the authors visualized echovirus 18 genome release inside infected cells, showing empty capsids lacking one or more pentamers 30 minutes post-infection, consistent with capsid opening. Neonatal Fc receptor binding expelled VP1 pocket factors in vitro, and pocket factors were absent in intracellular genome-containing particles, indicating receptor-triggered priming precedes rapid uncoating.
Impact: This is the first structural visualization of enteroviral genome release in infected cells, resolving a long-standing question in picornavirus biology and identifying capsid opening as the in vivo uncoating mechanism.
Clinical Implications: Defining receptor-triggered capsid opening and pocket factor expulsion as key steps suggests antiviral strategies targeting uncoating priming or stabilizing VP1 pocket factors to block enteroviral infection, including respiratory presentations.
Key Findings
- At 30 minutes post-infection, endosomes and cytoplasm contained empty E18 capsids missing one or several pentamers, indicating genome release via capsid opening in vivo.
- Neonatal Fc receptor (FcRn) binding in vitro expelled VP1 pocket factors, priming the virus for uncoating.
- Genome-containing particles inside cells lacked detectable pocket factors, supporting receptor-triggered priming during infection.
- Activated intermediates were not detected in cells, suggesting rapid uncoating in vivo.
Methodological Strengths
- In situ cryo-electron tomography and microscopy provide direct structural evidence in infected cells
- Integrated in vivo and in vitro receptor-binding and structural analyses strengthen mechanistic inference
Limitations
- Focused on a single enterovirus (E18); generalizability to other enteroviruses requires confirmation
- Cell culture system with limited temporal sampling may miss transient intermediates
Future Directions: Extend in situ structural analyses across diverse enteroviruses and receptors, and test uncoating inhibitors that stabilize VP1 pocket factors or block receptor-triggered priming in relevant in vivo models.
Enteroviruses cause a broad spectrum of human diseases, ranging from mild respiratory or gastrointestinal infections to severe neurological disorders such as aseptic meningitis and encephalitis. Enterovirus cell entry involves receptor-mediated endocytosis followed by destabilizing rearrangements of the virus capsid that enable genome release. However, the mechanism of enterovirus genome release has not been visualized in infected cells. Here, we used cryoelectron tomography and microscopy to image echovirus 18 (E18) entry into host cells and its interaction with the neonatal Fc receptor (FcRn). 30 min postinfection, endosomes and cytoplasm contained empty capsids missing one or several pentamers of capsid proteins, providing evidence that in vivo E18 releases its genome through capsid opening. In vitro, FcRn binding induced the expulsion of pocket factors from hydrophobic pockets in VP1, priming the virus for uncoating. The cryoelectron microscopy reconstruction of genome-containing particles of E18 inside infected cells did not reveal pocket factors, indicating that receptor binding triggers the same priming process during infection. We did not detect activated particles in infected cells, suggesting that these intermediates are short-lived and rapidly release their genomes in vivo. Our results identify capsid opening as the in vivo mechanism of echovirus 18 genome release, providing structural evidence for a process previously only inferred from in vitro experiments.
3. The Airway Transcriptome in Type 2 Cytokine Biomarker-High and -Low Severe Asthma.
Bronchial transcriptomics across severe asthma endotypes, adjusted for inhaled corticosteroid effects, revealed T2-high disease with elevated canonical T2 genes, epithelial barrier/keratin pathways, adaptive immunity, and ciliary dysfunction. T2-low disease showed Th1/IL‑17 and interferon-γ signaling, neuroimmune pathways, airway smooth muscle gene expression, and neutrophil enrichment; findings were validated in an external bronchoscopy cohort.
Impact: Defines steroid-independent airway molecular endotypes of severe asthma with direct implications for selecting and developing targeted biologics for T2-high and T2-low disease.
Clinical Implications: Supports endotype-driven therapy: T2-high patients align with anti-T2 biologics, whereas T2-low signatures suggest trials of therapies targeting Th1/IL‑17, interferon pathways, neuroimmune signaling, or airway smooth muscle remodeling.
Key Findings
- Severe asthma showed upregulation of mucins, CEACAM5, canonical T2 genes (POSTN, CLCA1, CCL26), epithelial mast cell genes, and CPA4 independent of ICS effects.
- T2-high endotype exhibited increased epithelial barrier/keratin genes, adaptive immune responses, and impaired ciliary function.
- T2-low endotype was characterized by Th1/IL‑17 and interferon-γ signaling, neuroimmune pathways, airway smooth muscle genes, and neutrophil enrichment.
- Results were validated using bronchoscopy data from the U-BIOPRED Consortium.
Methodological Strengths
- Bronchial biopsies and brushes with paired pre/post high-dose ICS assessment to control confounding
- External validation in an independent multicenter cohort (U-BIOPRED)
Limitations
- Sample sizes per endotype subgroup were modest, limiting power for some pathway analyses
- Observational design precludes causal inference and therapeutic validation
Future Directions: Prospective trials allocating biologics by molecular endotype and development of clinically deployable biomarker panels integrating airway and blood signatures.
Severe asthma is a heterogeneous disease. The mechanisms driving airway pathology when type 2 (T2) cytokine activity is suppressed remain poorly understood. This study aimed to provide insight by identifying the airway molecular pathways of T2 biomarker-high and -low severe asthma. We analysed clinical and transcriptomic data from bronchial biopsies and brushes in the UK Refractory Asthma Stratification Programme multi-centre severe asthma cohort (18 corticosteroid-resistant T2 biomarker-high [T2-high], 23 T2 biomarker-intermediate [T2-intermediate], 11 T2 biomarker-low [T2-low]) plus 20 healthy controls pre- and post-treatment with high-dose inhaled corticosteroids (ICS). Many genes dysregulated in asthma vs. health were concordantly dysregulated in healthy subjects receiving ICS. Severe asthma as a whole, independent of confounding by ICS, was characterised by upregulation of mucins, CEACAM5, typical T2-genes (POSTN, CLCA1, CCL26), epithelial mast cell genes, and CPA4. T2-high severe asthma demonstrated upregulated T2-dependent genes, epithelial barrier and keratin genes, adaptive immune responses, and impaired ciliary function. T2-low asthma showed upregulated Th1- and IL-17-associated genes (IDO1, CXCL10, GBP1, LAG3), interferon-γ signalling, neuroimmune pathways, airway smooth muscle-related genes, and neutrophil enrichment. T2-intermediate asthma exhibited a mixed molecular profile sharing features of T2-high and T2-low endotypes, with selective expression of the pathogen defence and antiviral response genes. The results were validated using bronchoscopy data from the U-BIOPRED Consortium. This study defines airway molecular endotypes of severe asthma associated with T2 biomarker high and low phenotypes, independent of corticosteroid effects. These findings offer insights for severe asthma management and the development of targeted biologic therapies.