Daily Respiratory Research Analysis

Summary

Three impactful respiratory studies stood out today: a pooled analysis of two randomized trials showed high-dose influenza vaccine reduced hospitalizations in older adults; real-world data demonstrated very high effectiveness of the RSVpreF vaccine against severe RSV-related acute respiratory illness; and a mechanistic PNAS study identified cytosolic PCNA as a central driver of neutrophil hyperactivation in severe COVID-19 with a small-molecule inhibitor suppressing NETosis.

Research Themes

Respiratory vaccine effectiveness and policy
Neutrophil-driven hyperinflammation mechanisms in COVID-19
Prevention of severe respiratory illness in older adults

Selected Articles

1. Effectiveness of high-dose influenza vaccine against hospitalisations in older adults (FLUNITY-HD): an individual-level pooled analysis.

85.5Level IMeta-analysisLancet (London, England) · 2025PMID: 41115437

In a prespecified pooled analysis of two harmonized, individually randomized pragmatic trials (n=466,320; ages ≥65), high-dose inactivated influenza vaccine reduced hospitalizations for influenza or pneumonia versus standard-dose (rVE 8.8%; 95% CI 1.7–15.5). HD-IIV also reduced cardiorespiratory hospitalizations, laboratory-confirmed influenza hospitalizations, and all-cause hospitalizations, with similar mortality and safety profiles.

Impact: This large, prespecified individual-level pooled analysis provides robust randomized evidence that HD-IIV confers superior protection against severe outcomes in older adults, supporting policy shifts toward high-dose vaccination.

Clinical Implications: For adults ≥65 years, preferential use of HD-IIV could reduce hospitalizations for influenza/pneumonia and cardiorespiratory causes without compromising safety, informing vaccine program procurement and recommendations.

Key Findings

Primary endpoint: influenza or pneumonia hospitalization reduced (0.56% HD-IIV vs 0.62% SD-IIV; rVE 8.8%, 95% CI 1.7–15.5).
Secondary: cardiorespiratory hospitalization reduced (2.02% vs 2.16%; rVE 6.3%, 95% CI 2.5–10.0).
Lab-confirmed influenza hospitalization reduced (0.11% vs 0.16%; rVE 31.9%, 95% CI 19.7–42.2).
All-cause hospitalization reduced (8.54% vs 8.73%; rVE 2.2%, 95% CI 0.3–4.1); mortality similar (0.61% vs 0.62%).
Serious adverse events were similar between groups.

Methodological Strengths

Prespecified individual-level pooled analysis of two harmonized, randomized pragmatic trials across multiple seasons and countries.
Large sample size (466,320) with routine healthcare databases enabling robust endpoint capture.

Limitations

Mortality was not reduced and the effect on pneumonia alone was small; absolute risk differences were modest.
Generalisability primarily to older adults in Denmark and Spain; results contingent on circulating strains/seasons.

Future Directions: Assess cost-effectiveness and equity impacts of switching to HD-IIV, evaluate performance across diverse regions/seasons, and integrate with coadministration strategies (e.g., RSV vaccines).

2. Cytosolic proliferating cell nuclear antigen (PCNA) orchestrates neutrophil hyperactivation in COVID-19.

80Level IVBasic/Mechanistic researchProceedings of the National Academy of Sciences of the United States of America · 2025PMID: 41118208

The study links elevated cytosolic PCNA in neutrophils from severe/critical COVID-19 to increased ROS and NETosis and shows that a PCNA-scaffold inhibitor (T2AA) markedly suppresses these responses, especially to SARS-CoV-2 RNA. A novel interaction between PCNA and calprotectin (S100A8/S100A9) is identified, providing a druggable axis for mitigating neutrophil-driven hyperinflammation.

Impact: Revealing a cytosolic PCNA–calprotectin axis that drives neutrophil hyperactivation is a notable mechanistic advance with immediate translational implications through a small-molecule inhibitor.

Clinical Implications: Targeting PCNA scaffolding may attenuate detrimental NETosis/oxidative bursts in severe viral pneumonias, potentially complementing anti-inflammatory therapies in COVID-19 and related conditions.

Key Findings

Cytosolic PCNA is elevated in neutrophils from severe/critical COVID-19 and correlates with enhanced ROS generation and NET formation.
T2AA, a PCNA-scaffold inhibitor, suppresses NADPH oxidase activation and NET release, especially in response to SARS-CoV-2 RNA.
Previously unrecognized interaction between PCNA and S100A8/S100A9 (calprotectin) identified in hyperactivated neutrophils.

Methodological Strengths

Multi-pronged approach integrating patient-derived neutrophils, pathway interrogation, and pharmacologic inhibition.
Mechanistic dissection identifying a specific protein–protein interaction as a therapeutic target.

Limitations

Sample sizes and patient cohort details are not provided in the abstract; external validation needed.
Translational efficacy and safety of T2AA or related inhibitors in vivo clinical settings remain untested.

Future Directions: Validate the PCNA–S100A8/S100A9 axis across cohorts, define structural interfaces for drug design, and test PCNA-scaffold inhibitors in relevant in vivo models and early-phase clinical trials.

3. Estimated Vaccine Effectiveness for Respiratory Syncytial Virus-Related Acute Respiratory Illness in Older Adults: Findings From the First Postlicensure Season.

70Level IICase-controlClinical infectious diseases : an official publication of the Infectious Diseases Society of America · 2025PMID: 41117531

In a retrospective test-negative study including 8,965 ARI ED visits/hospitalizations among adults ≥60 years, RSVpreF vaccination ≥21 days prior was associated with 92% VE (95% CI 64–98) against RSV-related ARI. High VE persisted in high-risk individuals, those ≥75 years, and for critical outcomes (e.g., ICU admission, mechanical ventilation, respiratory failure, vasopressors, or death).

Impact: This is the first postlicensure season effectiveness estimate showing very high protection of RSVpreF in older adults across severe endpoints, supporting implementation and uptake in high-risk populations.

Clinical Implications: Clinicians and health systems can confidently recommend RSVpreF to adults ≥60 years, particularly those ≥75 or with comorbidities, to prevent severe RSV-related ARI requiring ED care or hospitalization.

Key Findings

Adjusted VE against RSV-related ARI ED visits/hospitalizations was 92% (95% CI 64–98).
High VE in patients with risk conditions (92%), in those ≥75 years (95%), and for critical outcomes (90%).
Only 0.3% of RSV-positive cases vs 3.6% of controls had received RSVpreF ≥21 days prior.

Methodological Strengths

Test-negative design reduces bias from healthcare-seeking behavior and differential testing.
Large integrated health system with laboratory-confirmed outcomes and multivariable adjustment.

Limitations

Retrospective observational design subject to residual confounding and potential misclassification.
Single health system and one season limit generalizability; vaccine uptake and timing may bias estimates.

Future Directions: Evaluate durability across seasons, comparative effectiveness with other RSV vaccines, and effect on long-term outcomes (e.g., post-viral complications) across diverse populations.