Respiratory Research Analysis
March respiratory research delivered practice-shaping clinical evidence and transmission/immunogen insights. A large pragmatic phase 3 trial (PRONTO) showed that adding rapid procalcitonin to NEWS2-based ED care reduced 28-day mortality in suspected sepsis, while extended randomized follow-up from FIBRONEER-ILD showed nerandomilast reduced the composite of AE-ILD, respiratory hospitalization, and death in progressive pulmonary fibrosis. Bedside precision advanced with PHIND, where near-patient I
Summary
March respiratory research delivered practice-shaping clinical evidence and transmission/immunogen insights. A large pragmatic phase 3 trial (PRONTO) showed that adding rapid procalcitonin to NEWS2-based ED care reduced 28-day mortality in suspected sepsis, while extended randomized follow-up from FIBRONEER-ILD showed nerandomilast reduced the composite of AE-ILD, respiratory hospitalization, and death in progressive pulmonary fibrosis. Bedside precision advanced with PHIND, where near-patient IL-6/sTNFR1 testing classified ARDS subphenotypes within an hour with strong mortality separation. Mechanistic and translational studies refined prevention strategies: controlled human influenza infection directly quantified heterogeneous infectious aerosol emission, and drift-resilient, RBS-mimicking broadly neutralizing antibodies against influenza B informed next-generation immunogen design.
Selected Articles
1. Procalcitonin testing combined with NEWS2 evaluation compared with usual care based on NEWS2 for identification of sepsis and antibiotic initiation in the emergency department in England and Wales (PRONTO): a multicentre, randomised, controlled, open-label, phase 3 trial.
In a pragmatic multicenter phase 3 trial (>7,600 randomized; 5,453 analyzed for co-primary endpoints), adding rapid procalcitonin testing to NEWS2-based emergency care did not change 3-hour IV antibiotic initiation but significantly reduced 28-day mortality (13.6% vs 16.6%; adjusted risk difference −3.12 percentage points), meeting non-inferiority and superiority criteria without increasing adverse events.
Impact: A large, pragmatic randomized trial shows that integrating a rapid biomarker into routine ED assessment improves survival in suspected sepsis, offering immediate pathway and guideline implications.
Clinical Implications: EDs should consider workflow integration of rapid procalcitonin with monitoring of adherence, stewardship, and outcomes; mortality can be reduced without increasing early antibiotic initiation.
Key Findings
- 28-day mortality was significantly lower with procalcitonin-guided care.
- 3-hour IV antibiotic initiation rates were similar between groups.
- Adverse events were comparable; clinicians used PCT in most guided decisions.
2. Nerandomilast in progressive pulmonary fibrosis: data from the whole follow-up period of the FIBRONEER-ILD trial.
In 1,176 patients with progressive pulmonary fibrosis and mean 17 months observation, nerandomilast reduced the composite risk of first acute ILD exacerbation, respiratory hospitalization, or death (HRs ~0.77–0.78 versus placebo) with a favorable tolerability profile; benefits were larger in patients not on background nintedanib.
Impact: Extended randomized follow-up shows a disease-modifying antifibrotic reduces hard clinical endpoints, positioning nerandomilast as a potential practice-changing option in PPF.
Clinical Implications: Consider nerandomilast—particularly without background nintedanib—as a strategy to reduce AE-ILD, respiratory hospitalization, and death, with structured monitoring for long-term safety.
Key Findings
- Reduced composite of AE-ILD, respiratory hospitalization, or death versus placebo.
- Greater effect size without background nintedanib.
- Favorable safety and tolerability over extended follow-up.
3. Bedside identification of subphenotypes in acute respiratory failure (PHIND): a multicentre, observational cohort study.
In a prospective multicentre ICU cohort (n=512 phenotyped), a near-patient benchtop immunoanalyser measuring IL-6 and sTNFR1, combined with bicarbonate and a parsimonious model, classified ARDS/AHRF into hyperinflammatory (~18%) and hypoinflammatory groups within ~1 hour. Hyperinflammatory patients had markedly higher 60-day mortality (51% vs 28%; adjusted OR 2.7), demonstrating feasibility and strong prognostic separation for bedside phenotyping.
Impact: First large, prospective, bedside-capable ARDS subphenotyping with clear mortality separation, enabling phenotype-stratified trials and actionable ICU decision-making.
Clinical Implications: Rapid IL-6/sTNFR1 testing can feasibly stratify ARDS patients for prognosis and trial enrollment; hyperinflammatory patients may be prioritized for immunomodulatory strategies.
Key Findings
- One-hour near-patient testing sorted ARDS/AHRF into hyper- vs hypoinflammatory phenotypes.
- Hyperinflammatory phenotype had substantially higher 60-day mortality.
- Feasibility and turnaround demonstrated across multiple centers.
4. Controlled human influenza infection reveals heterogeneous expulsion of infectious virus into air.
Using a modular influenza sampling tunnel (MIST), investigators directly captured, cultured, quantified and sequenced infectious influenza virus from exhaled particles of experimentally infected humans. Expelled infectious loads varied across individuals by orders of magnitude, correlated with infectious viral loads in saliva/nasopharynx and with symptoms, and preserved within-host viral diversity in aerosols.
Impact: Rare, direct human data link emission magnitude to clinical/virologic markers, refining transmission risk models and enabling targeted infection prevention strategies.
Clinical Implications: IPC should account for high emitters and symptom-linked peaks (targeted masking, ventilation, testing), and surveillance can prioritize contexts with high expulsion potential.
Key Findings
- Culture-based quantification and sequencing of infectious virus from exhaled particles in humans.
- Infectious emission varied by orders of magnitude across individuals.
- Emission correlated with infectious loads in saliva/nasopharynx and with symptoms.
5. Human monoclonal antibodies isolated after seasonal vaccination broadly neutralize antigenically drifted influenza B viruses.
Two human broadly neutralizing antibodies (CAV‑CF22, CAV‑CH76) isolated after quadrivalent vaccination neutralize contemporary Victoria and Yamagata influenza B lineages and protect in vivo. Structural analyses show these antibodies insert HCDR3 into the HA receptor-binding site to sterically mimic sialic acid, conferring breadth and resilience to K136E drift and informing drift-resistant vaccine and therapeutic design.
Impact: Reveals a drift-resilient neutralization mechanism at the HA RBS, providing bnAb candidates and a blueprint for next-generation influenza B immunogens and therapeutics.
Clinical Implications: Guides immunogen design toward conserved RBS features and supports therapeutics robust to K136E drift; surveillance of HA‑136 variants should inform vaccine updates.
Key Findings
- Two human bnAbs neutralized Victoria and Yamagata lineages and protected in vivo.
- High-resolution structures showed HCDR3 insertion into the RBS to mimic sialic acid.
- Fixation of K136E in Victoria HA disrupted many prior head-directed epitopes.