Daily Respiratory Research Analysis
Three impactful respiratory studies stand out today: a Nature Communications re-analysis shows lung cancer screening effectiveness varies markedly by smoking history, sex, and, critically, tumor histology. Two large pragmatic randomized trials from Europe report that high-dose influenza vaccination consistently outperforms standard-dose across cardiovascular subgroups, and that an RSV prefusion F vaccine has similar effectiveness in older adults with or without atherosclerotic cardiovascular dis
Summary
Three impactful respiratory studies stand out today: a Nature Communications re-analysis shows lung cancer screening effectiveness varies markedly by smoking history, sex, and, critically, tumor histology. Two large pragmatic randomized trials from Europe report that high-dose influenza vaccination consistently outperforms standard-dose across cardiovascular subgroups, and that an RSV prefusion F vaccine has similar effectiveness in older adults with or without atherosclerotic cardiovascular disease.
Research Themes
- Heterogeneity in lung cancer screening effectiveness driven by histology
- Optimization of respiratory virus vaccination strategies in older adults
- Cardiovascular–respiratory interface in vaccine outcomes
Selected Articles
1. High-dose vs. standard-dose inactivated influenza vaccine and cardiovascular outcomes in persons with or without pre-existing atherosclerotic cardiovascular disease: the DANFLU-2 trial.
In a large pragmatic randomized trial across three influenza seasons, high-dose inactivated influenza vaccine reduced influenza-related hospitalizations compared with standard-dose with consistent relative effectiveness in patients with and without ASCVD. Cardiovascular outcomes (MACE) showed no significant heterogeneity by ASCVD status.
Impact: This head-to-head randomized evidence supports preferential use of high-dose influenza vaccine in older adults regardless of ASCVD, informing vaccination policy for respiratory infection prevention and potential cardioprotection.
Clinical Implications: For adults ≥65 years, high-dose influenza vaccine can be favored over standard-dose to reduce influenza-related hospitalizations irrespective of ASCVD status, simplifying vaccine selection in primary and cardiovascular care settings.
Key Findings
- High-dose IIV showed substantially higher effectiveness for influenza hospitalization than standard-dose in both ASCVD and non-ASCVD groups.
- No significant interaction by ASCVD status for respiratory or cardiovascular outcomes (all Pinteraction ≥ .05).
- MACE relative vaccine effectiveness estimates were small and similar regardless of ASCVD (no statistically significant difference).
Methodological Strengths
- Pragmatic, individually randomized design with nationwide registry ascertainment across three seasons
- Large sample size enabling robust subgroup analyses by ASCVD status
Limitations
- Open-label design may introduce behavior or ascertainment bias
- Exploratory prespecified analysis; primary endpoints not powered specifically for ASCVD interaction
Future Directions: Assess cost-effectiveness and implementation strategies for scaling high-dose influenza vaccination in multimorbid older adults, and explore additive benefits with RSV vaccination.
BACKGROUND AND AIMS: The aim was to evaluate and compare the relative vaccine effectiveness (rVE) of high-dose (HD-IIV) vs. standard-dose inactivated influenza vaccination (SD-IIV) on respiratory and cardiovascular outcomes in persons with or without pre-existing atherosclerotic cardiovascular disease (ASCVD). METHODS: A prespecified exploratory analysis of a pragmatic, open-label, individually randomized trial conducted in Denmark during three influenza seasons. Adults ≥65 years were randomized 1:1 to HD-IIV or SD-IIV. Baseline and outcome data were collected through nationwide registries. The primary outcome was hospitalization for influenza or pneumonia. Major adverse cardiovascular events (MACE) was defined as a composite of cardiovascular death, hospitalization for myocardial infarction, or hospitalization for stroke. Heterogeneity in rVE among participants with vs. without ASCVD was assessed. RESULTS: The incidence of all outcomes was higher in participants with pre-existing ASCVD (n = 46 825) vs. those without (n = 285 613). rVE was consistent among participants with and without ASCVD (all Pinteraction ≥ .05). The rVE for the primary outcome was 6.87% [95% confidence interval (CI), -2.52 to 15.42] among individuals without ASCVD and 4.71% (95% CI, -11.58 to 18.63) in those with (Pinteraction = .80). For influenza hospitalizations, the rVE was 42.88% (95% CI, 22.07-58.44) vs. 45.73% (95% CI, 16.68-65.16) in those without vs. with ASCVD (Pinteraction = .84). For MACE, the rVE was 4.29% (95% CI, -6.50 to 14.00) in participants without, and 0.30% (95% CI, -17.56 to 15.44) in participants with, pre-existing ASCVD (Pinteraction = .68). CONCLUSIONS: Among individuals ≥65 years, the rVE of HD-IIV vs. SD-IIV against respiratory and cardiovascular outcomes was similar among those with vs. without pre-existing ASCVD.
2. A comparative analysis of heterogeneity in lung cancer screening effectiveness in two randomised controlled trials.
Using individual-level data from NLST and NELSON, the authors show that lung cancer screening mortality reduction varies substantially by pack-years, smoking status, sex, and, most critically, by histology. The heterogeneity across subgroups is largely explained by differing distributions of histologic subtypes with more favorable screening responsiveness.
Impact: This study reframes eligibility and evaluation for lung cancer screening by demonstrating histology-driven effectiveness, informing tailored screening policies beyond simple smoking thresholds.
Clinical Implications: Screening programs should consider histology-driven benefits when refining eligibility (e.g., relaxing smoking criteria) and when communicating expected benefit by patient subgroup, potentially improving population effectiveness.
Key Findings
- Mortality reduction varied by pack-years, smoking status, and sex across NLST and NELSON.
- Histology was the dominant driver: adenocarcinoma and non-squamous subtypes showed greater benefit; small-cell and, in NLST, squamous-cell carcinoma showed limited/negative benefit.
- Subgroup heterogeneity was largely attributable to differences in histologic distributions within those subgroups.
Methodological Strengths
- Individual participant data from two landmark randomized screening trials
- Multiple analytic approaches including traditional subgrouping, predictive modeling, and machine learning
Limitations
- Post hoc comparative analyses may be sensitive to model assumptions and confounding in cross-trial comparisons
- Histology-based inferences depend on accurate classification and may not capture intra-tumor heterogeneity
Future Directions: Prospective evaluation of histology-informed eligibility and decision tools; assess program-level impact of relaxing smoking criteria while safeguarding harms.
Clinical trials demonstrate that screening can reduce lung cancer mortality by over 20%. However, lung cancer screening effectiveness (reduction in lung cancer specific mortality) may vary by personal risk-factors. Here we evaluate heterogeneity in lung cancer screening effectiveness through traditional sub-group analyses, predictive modelling approaches and machine-learning in individual-level data from the Dutch-Belgian lung cancer screening trial (NELSON; 14,808 participants, 12,429 men, 2377 women, 2 persons with an unknown sex) and the National Lung Screening Trial (NLST; 53,405 participants, 31,501 men, 21,904 women). We find that screening effectiveness varies by pack-years (screening effectiveness ranges across trials: lowest groups = 26.8-50.9%, highest groups = 5.5-9.5%), smoking status (screening effectiveness ranges across trials: former smokers = 37.8-39.1%, current smokers = 16.1-22.7%) and sex (screening effectiveness ranges across trials: women = 24.6-25.3%; men = 8.3-24.9%). Furthermore, screening effectiveness varies by histology (screening effectiveness ranges across trials: adenocarcinoma = 17.8-23.0%, other lung cancers = 24.5-35.5%, small-cell carcinoma = 9.7%-11.3%). Screening is ineffective for squamous-cell carcinoma in NLST (screening effectiveness = 27.9% (95% confidence interval: 69.8% increase to 4.5% decrease) mortality increase) but effective in NELSON (screening effectiveness = 52.2% (95% confidence interval: 25.7-69.1% decrease) mortality reduction). We find that variations in screening effectiveness across pack-years, smoking status, and sex are primarily explained by a greater prevalence of histologies with favourable screening effectiveness in these groups. Our study shows that heterogeneity in lung screening effectiveness is primarily driven by histology and that relaxing smoking-related screening eligibility criteria may enhance screening effectiveness.
3. Effectiveness of bivalent respiratory syncytial virus prefusion F protein-based vaccine in individuals with or without atherosclerotic cardiovascular disease: the DAN-RSV trial.
In this prespecified secondary analysis of a large randomized registry-based trial, RSVpreF vaccination markedly reduced RSV-related respiratory hospitalizations with similar effectiveness in older adults regardless of ASCVD status. Major cardiovascular event reduction was small and did not differ by ASCVD.
Impact: Supports broad RSV vaccination of older adults including those with ASCVD, simplifying prioritization without compromising benefit in high-risk cardiovascular populations.
Clinical Implications: Clinicians can recommend RSVpreF broadly to ≥60-year-olds irrespective of ASCVD; counseling should note strong respiratory protection and uncertain/limited MACE impact.
Key Findings
- RSVpreF markedly reduced RSV-related respiratory tract hospitalization; VE was similar with and without ASCVD.
- No significant interaction by ASCVD for respiratory or cardiovascular outcomes.
- Effect on major adverse cardiovascular events was modest and not statistically significant in either subgroup.
Methodological Strengths
- Randomized allocation with nationwide registry ascertainment and prespecified subgroup analysis
- Very large sample enabling precise estimation across ASCVD strata
Limitations
- Secondary analysis; some VE estimates have wide confidence intervals (especially in ASCVD subgroup)
- Open-label vaccination strategy may introduce residual confounding in healthcare-seeking behaviors
Future Directions: Evaluate durability across multiple RSV seasons and potential additive value when co-administered with influenza vaccines in high-risk multimorbid elders.
BACKGROUND AND AIMS: It is not known whether the bivalent respiratory syncytial virus prefusion F protein-based (RSVpreF) vaccine reduces outcomes in individuals with atherosclerotic cardiovascular disease (ASCVD). The aim was to evaluate the vaccine effectiveness (VE) of an RSVpreF vaccine vs no vaccine on respiratory and cardiovascular outcomes in persons with or without pre-existing ASCVD. METHODS: We conducted a prespecified secondary analysis of the DAN-RSV trial. Adults aged ≥60 years were randomized 1:1 to RSVpreF vaccine or no vaccine. Baseline and outcome data were collected through nationwide registries. The primary outcome was respiratory syncytial virus-related respiratory tract disease hospitalization. The principal major adverse cardiovascular event outcome was a composite of hospitalization for myocardial infarction, stroke, or heart failure. Heterogeneity in VE was assessed among participants with and without ASCVD. RESULTS: The incidence rate of almost all outcomes was higher in participants with pre-existing ASCVD (n = 14 241) vs those without (n = 117 035). Vaccine effectiveness was generally consistent by ASCVD status (Pinteraction ≥ .05 for all but one interaction). Among persons without and with ASCVD, VE for the primary outcome was 80.0% [95% confidence interval (CI, 29.3-96.3] vs 100.0% (95% CI, -141.3 to 100.0), respectively (Pinteraction > .99). Vaccine effectiveness for major adverse cardiovascular events was 9.3% (95% CI, -15.1 to 28.6) in participants without, and 12.0% (95% CI, -34.6 to 43.3) in participants with, pre-existing ASCVD (Pinteraction = .90). CONCLUSIONS: The VE of an RSVpreF vaccine vs no vaccine against respiratory and cardiovascular outcomes was similar among individuals ≥ 60 years of age with pre-existing ASCVD as compared with those without.