Daily Respiratory Research Analysis
Analyzed 66 papers and selected 3 impactful papers.
Summary
Three high-impact respiratory studies span transmission science, precision critical care, and antiviral therapeutics. Filamentous influenza A virions show superior aerosol stability and mucosal infectivity, real-time ARDS subphenotyping is feasible across US hospitals within hours, and a nanobody-PROTAC platform achieves broad-spectrum anti-influenza efficacy with in vivo survival benefits.
Research Themes
- Aerosol stability and morphology-driven transmissibility of respiratory viruses
- Real-time biological subphenotyping enabling precision trials in ARDS/AHRF
- Broad-spectrum antiviral strategies via targeted protein degradation
Selected Articles
1. Filamentous morphology of influenza A virus confers enhanced stability in aerosols.
Filamentous IAVs resist physicochemical inactivation in submicron aerosols, particularly at 80% RH and low pH, and retain infectivity advantages under mucus and neutralizing antibodies in primary human airway cultures. Morphology thus directly contributes to airborne stability and epithelial infectivity.
Impact: This study mechanistically links virion morphology to aerosol stability and mucosal infectivity, advancing understanding of airborne transmission and informing control strategies.
Clinical Implications: Highlights the potential for filamentous-dominant strains to persist in indoor aerosols and evade mucosal defenses, suggesting implications for ventilation standards, humidity control, and personal protective strategies.
Key Findings
- Filamentous IAVs exhibited enhanced stability in submicron aerosols at 80% relative humidity and in bulk solutions mimicking increased salinity.
- Acidic conditions caused slower infectivity decay for filamentous vs spherical virions in both aerosols and bulk solutions.
- In primary human airway cultures, filamentous IAVs showed infectivity advantages under mucosal immune pressures (neutralizing antibodies, mucus).
Methodological Strengths
- Integrated aerosol microphysics with bulk-solution assays across RH and pH conditions.
- Validation in primary human airway cultures under physiologic mucosal pressures.
Limitations
- Laboratory aerosol systems may not fully recapitulate real-world indoor environments.
- Morphological distribution depends on strain and growth conditions, potentially limiting generalizability.
Future Directions: Assess morphology distributions in clinical isolates over time, quantify impacts of ventilation/filtration and humidity in built environments, and model transmission risk incorporating morphological heterogeneity.
Airborne transmission of influenza A virus (IAV) poses significant challenges to public health. However, the mechanisms governing viral inactivation in aerosols remain poorly understood. IAVs exhibit morphological variability, ranging from 100 nm spherical virions to micrometer-long filaments, depending on strain and growth conditions. Although virion morphology was shown to influence transmissibility, the mechanisms of how morphology affects airborne transmission are yet to be delineated. Here, we investigated the impact of virion shape on IAV stability in bulk solutions and an aerosol system with a focus on particles in the submicrometer range to examine how physicochemical aerosol properties, such as elevated solute concentration and low pH, affect infectivity. We show that filamentous viruses exhibit enhanced stability in aerosol particles at 80% relative humidity (RH) and in bulk solution mimicking increased salinity at this RH. Similarly, filamentous viruses exhibited slower decay under acidic conditions, both in bulk solutions and in acidified aerosol particles. Using primary human airway cultures, we further found that filamentous IAVs possess an infectivity advantage under mucosal immune pressures, including neutralizing antibodies and mucus. These results reveal that filamentous shape provides IAV with enhanced stability under diverse environmental conditions in the aerosol phase and increased infectivity in the respiratory epithelium.
2. Biological subphenotypes in severe acute hypoxaemic respiratory failure and acute respiratory distress syndrome using rapid prospective classification (SPARC) in the USA: a multicentre, observational, study.
In a 17-hospital US network, real-time ARDS/AHRF subphenotyping using IL-6, TNFR1, and clinical variables was feasible within a median of 2.2 hours, with success rates improving from 59% to 82% over time. Hyperinflammatory ARDS constituted 29% and was associated with worse mortality and fewer organ- and ventilator-free days.
Impact: Demonstrates operational feasibility of rapid biological subphenotyping at scale, enabling precision enrollment and targeted therapies in future ARDS trials.
Clinical Implications: Supports integrating rapid biomarker panels (IL-6, TNFR1) into care pathways to identify hyperinflammatory ARDS with worse prognosis and to inform stratified trial designs.
Key Findings
- Among 338 enrolled patients across 17 hospitals, 250 (74%) achieved real-time subphenotype assignment using fresh plasma.
- Operational feasibility improved over time: successful subphenotyping increased from 59% (first 100) to 82% (last 100).
- Hyperinflammatory ARDS comprised 29% and was associated with worse mortality and fewer organ- and ventilator-free days.
- Median time from blood collection to assignment was 2.2 hours overall and 1.9 hours among successfully subphenotyped patients.
Methodological Strengths
- Prospective multicentre cohort with predefined feasibility metrics and rapid plasma biomarker testing.
- Real-time workflow integration demonstrating scalability across diverse hospitals.
Limitations
- Observational design without interventional testing of subphenotype-guided therapy.
- Demographic skew (majority White) may limit generalizability; one-third not successfully subphenotyped.
Future Directions: Embed subphenotype-guided randomised trials, expand biomarker panels, and validate performance across broader, diverse populations and non-COVID etiologies.
BACKGROUND: Two biological subphenotypes in acute respiratory distress syndrome (ARDS) have been identified in retrospective analyses, with differential clinical outcomes and post-hoc responses to investigational treatments. The ability to identify biological subphenotypes in real-time is unknown. We aimed to evaluate the feasibility of using the multisite ISPY COVID Network to prospectively evaluate biological subphenotypes in real-time. METHODS: This prospective, observational, cohort study enrolled patients with ARDS and severe acute hypoxaemic respiratory failure (AHRF) and assessed the feasibility of real-time stratification into biological subphenotypes using plasma concentrations of IL-6, soluble tumour necrosis factor-1 (TNFR1), and clinical variables. Participants were eligible if they were receiving mechanical ventilation, non-invasive positive pressure ventilation, or heated high flow nasal oxygen (at flow rates ≥30 L/min); had severe AHRF (defined by an SpO FINDINGS: From June 15, 2023, to Oct 31, 2024, 844 patients at 17 hospitals in the ISPY COVID Network across the USA were screened for the study. After 504 exclusions and two withdrawals of consent, 338 patients were enrolled. 124 (37%) of the enrolled cohort were classified as AHRF, and 214 (63%) were classified as ARDS. 199 (59%) of patients were male and 138 (41%) were female, and the median age at enrolment was 64 years (IQR 54-74). The majority of patients were white (239 [71%]). 250 (74%) of the enrolled cohort completed subphenotype assignment using fresh plasma and were defined as successfully subphenotyped. Successful real-time subphenotyping increased from 59 for the first 100 enrolled participants (59% [95% CI 49-69]) to 82 for the last 100 enrolled participants (82% [73-89]), meeting the predefined feasibility threshold. Median time to subphenotype assignment from blood collection in the overall cohort and the successfully subphenotyped subgroup was 2·2 h (IQR 1·5-19·8) and 1·9 h (1·3-2·3) from the time of blood collection, respectively. The hyperinflammatory subphenotype was identified in 61 (29%) of 214 participants with ARDS and 29 (23%) of the 124 participants with severe AHRF. Clinical outcomes including mortality, organ support-free days and ventilator-free days were worse in patients with hyperinflammatory ARDS compared with those with hypoinflammatory ARDS. INTERPRETATION: Rapid real-time biological subphenotyping for ARDS and severe AHRF in a multisite US hospital network is feasible; and successful real-time subphenotyping both improved over the study time-course and was completed within 2·2 h from study blood collection. These results support the feasibility of real-time precision trials of therapies targeting biological subphenotypes in ARDS. FUNDING: COVID R&D Consortium, Allergan, Amgen, Takeda Pharmaceutical Company, Ingenus Pharmaceuticals, Implicit Bioscience, Johnson & Johnson, Pfizer, Roche-Genentech, Apotex, FAST Grant from Emergent Venture George Mason University, and The Grove Foundation. This work was supported by the US Defense Threat Reduction Agency (MCDC-2013-001). This project has been funded in whole or in part with Federal funds from the US Department of Health and Human Services; Administration for Strategic Preparedness and Response; and Biomedical Advanced Research and Development Authority (MCDC-2014-001).
3. A nanobody-based proteolysis-targeting chimera offers broad-spectrum protection against diverse influenza virus infections.
Two Nb-PROTACs (VHL-Nb135, VHL-Nb170) degrade influenza NP across all H1–H16 subtypes, suppressing replication of human and avian strains in vitro. Intratracheal AAV-LungM3 delivery of VHL-Nb170 markedly reduced respiratory tract viral loads and achieved 90% (H1N1) and 80% (H5N1) survival in lethal mouse models.
Impact: Introduces a broadly acting antiviral modality via targeted protein degradation with strong in vivo efficacy, offering a plausible path toward pan-influenza therapeutics.
Clinical Implications: Although preclinical, intrapulmonary gene-delivered Nb-PROTACs could complement vaccines and neuraminidase/polymerase inhibitors, particularly against antigenically drifted or zoonotic strains.
Key Findings
- VHL-Nb135 and VHL-Nb170 induced NP degradation across all 16 influenza A subtypes (H1–H16).
- Both chimeras inhibited replication of human (H1N1, H3N2) and avian (H5N1, H7N9, H9N2) strains in vitro.
- Intratracheal AAV-LungM3 delivery of VHL-Nb170 reduced respiratory viral loads and yielded 90% (H1N1) and 80% (H5N1) survival in lethal mouse models.
Methodological Strengths
- Cross-subtype validation spanning all H1–H16 influenza A subtypes.
- In vivo efficacy demonstrated with targeted intrapulmonary gene delivery.
Limitations
- Preclinical models; human safety, immunogenicity, and dosing remain unknown.
- AAV-based delivery may pose manufacturing, targeting, and repeat-dosing constraints.
Future Directions: Evaluate safety and pharmacodynamics in large-animal models, explore non-viral delivery platforms, and assess resistance barriers and combination strategies.
Influenza A viruses continue to pose a major threat to global public health. In addition to H1N1 and H3N2 subtypes causing seasonal epidemics that result in an estimated 3-5 million severe cases and 290,000-650,000 deaths annually, other subtypes, including avian H5, H7, and H9, have shown cross-species transmission potential, leading to thousands of human infections in multiple countries. The development of broad-spectrum antiviral drugs capable of inhibiting different influenza virus subtypes is key for alleviating the severity of diseases caused by influenza viruses and reducing mortality rates. Here, we constructed five nanobody-based proteolysis-targeting chimeras (Nb-PROTACs) by fusing NP-specific nanobodies to the α-domain of the Von Hippel‒Lindau (VHL) E3 ubiquitin ligase. We found that two of these chimeras (VHL-Nb135 and VHL-Nb170) efficiently induced NP degradation across all 16 recognized influenza A subtypes (H1-H16). VHL-Nb135 and VHL-Nb170 efficiently inhibited the replication of human (H1N1, H3N2) and avian (H5N1, H7N9, H9N2) influenza viruses in vitro. In animal studies, when VHL-Nb170 was administered intratracheally to mice via adeno-associated virus serotype LungM3 (AAV-LungM3), virus replication was significantly inhibited in the respiratory tract, and 90% and 80% of the mice survived infection with lethal H1N1 and H5N1 viruses, respectively. Our study indicates that Nb-PROTACs offer a robust platform for the development of broad-spectrum therapies against influenza viruses and hold potential for clinical translation as innovative antiviral candidate drugs.