Daily Respiratory Research Analysis
Three studies advance respiratory science and practice: a multicentre test-negative case-control study in England shows high effectiveness of an RSV pre-F vaccine against hospital admission and chronic disease exacerbations in adults aged 75–79; an autopsy-based investigation reveals tissue-specific SARS-CoV-2 spike adaptations in an immunodeficient patient, highlighting within-host evolution outside the respiratory tract; and a prospective biomarker study questions the interchangeability of ARD
Summary
Three studies advance respiratory science and practice: a multicentre test-negative case-control study in England shows high effectiveness of an RSV pre-F vaccine against hospital admission and chronic disease exacerbations in adults aged 75–79; an autopsy-based investigation reveals tissue-specific SARS-CoV-2 spike adaptations in an immunodeficient patient, highlighting within-host evolution outside the respiratory tract; and a prospective biomarker study questions the interchangeability of ARDS biological subphenotype models in Asian populations.
Research Themes
- Respiratory virus prevention and vaccine effectiveness in older adults
- Within-host viral evolution and tissue compartmentalization of SARS-CoV-2
- Generalizability of ARDS biological subphenotypes across ancestries
Selected Articles
1. Vaccine effectiveness of a bivalent respiratory syncytial virus (RSV) pre-F vaccine against RSV-associated hospital admission among adults aged 75-79 years in England: a multicentre, test-negative, case-control study.
In a multicentre test-negative analysis of 1,006 adults aged 75–79, the bivalent RSV pre-F vaccine reduced RSV-associated hospital admissions by 82.3% overall and 86.7% among severe cases requiring oxygen. Effectiveness extended to lower respiratory tract infection (88.6%) and to exacerbations of chronic lung (77.4%) and cardiac/pulmonary/frailty conditions (78.8%), with 72.8% effectiveness in immunosuppressed individuals.
Impact: Provides robust real-world effectiveness data in a vaccine-eligible older cohort, including prevention of exacerbations across chronic conditions and benefit in immunosuppressed patients.
Clinical Implications: Supports prioritizing RSV pre-F vaccination in adults ≥75 years and those with chronic cardiopulmonary diseases or immunosuppression. Findings justify integrating RSV vaccination into winter respiratory protection plans and targeting high-risk groups to prevent hospitalizations and exacerbations.
Key Findings
- Overall vaccine effectiveness against RSV-associated ARI hospitalisation: 82.3% (95% CI 70.6–90.0).
- Effectiveness against severe disease requiring oxygen: 86.7% (95% CI 75.4–93.6).
- Effectiveness for lower respiratory tract infection including pneumonia: 88.6% (95% CI 75.6–95.6).
- Effectiveness against exacerbations: chronic lung disease 77.4%, combined cardiac/lung/frailty 78.8%.
- Effectiveness in immunosuppressed adults: 72.8% (95% CI 39.5–89.3).
Methodological Strengths
- Multicentre test-negative case-control design within a national sentinel surveillance network.
- Standardized molecular testing within 48 hours of admission and structured clinical phenotyping, enabling endpoint-specific VE estimates.
Limitations
- Restricted to adults aged 75–79 years, limiting generalizability to other age groups.
- Observational design with potential residual confounding; subgroup sample sizes may be limited.
Future Directions: Assess durability of protection across seasons, effectiveness against mortality and ICU admission, performance across broader age bands and comorbidity strata, and cost-effectiveness for policy refinement.
2. Tissue tropism and functional adaptation of the SARS-CoV-2 spike protein in a fatal case of COVID-19.
Sequencing of SARS-CoV-2 from 27 tissues in an immunodeficient fatal case revealed tissue-specific genotypes, often with receptor-binding domain mutations. Computational and experimental data indicated spike substitutions that increase protein stability and host cell binding, supporting the concept of compartmentalized evolution in non-respiratory tissues.
Impact: Provides mechanistic insight into within-host SARS-CoV-2 evolution and tissue compartmentalization with functional validation, informing variant emergence risk in immunocompromised hosts.
Clinical Implications: Highlights the need for aggressive antiviral management and vigilant infection control in immunocompromised patients to limit prolonged replication and diversification. Encourages multi-site sampling in persistent infections and consideration of non-respiratory reservoirs.
Key Findings
- Tissue-specific SARS-CoV-2 genotypes identified across 27 autopsy tissues from an immunodeficient patient, with coexistence of variants at single sites.
- Spike receptor-binding domain mutations predominated; modeling and virus isolation supported increased spike stability and host receptor binding.
- Evidence of compartmentalized viral evolution in non-respiratory tissues underscores potential reservoirs driving diversification.
Methodological Strengths
- Extensive multi-organ sampling with high-depth genomic sequencing linked to protein simulations and isolation of infectious virus.
- Integrated analysis of viral population dynamics across tissues to infer compartmentalization.
Limitations
- Single-case autopsy from an immunodeficient host limits generalizability; postmortem interval and sampling may introduce bias.
- Lacks longitudinal pre-mortem sampling to directly track temporal evolution.
Future Directions: Longitudinal multi-compartment sampling in immunocompromised patients under antiviral therapy; mapping fitness landscapes of spike mutations by tissue; testing strategies to eradicate extra-pulmonary reservoirs.
3. Generalisability of ARDS biological subphenotype models in Asians: an international, multicentre, prospective biomarker study.
In 356 ARDS patients enrolled prospectively in Beijing and Pittsburgh, established subphenotype models yielded broadly similar hyper- vs hypoinflammatory distributions in Asians but showed poor agreement between classifiers. Asian Berlin-definition ARDS exhibited higher inflammatory profiles than HFNC-ARDS, underscoring heterogeneity within definitions.
Impact: Provides the first prospective cross-ancestry assessment of ARDS subphenotype classifiers in Asians, revealing poor intermodel agreement and emphasizing the need for harmonized, validated tools before bedside use.
Clinical Implications: Clinicians and trialists should avoid assuming interchangeability of ARDS classifiers across populations. Harmonized biomarker panels and unified models are needed to reliably stratify patients for prognostic enrichment and therapy selection.
Key Findings
- Prospective bi-national cohort (n=356) showed similar predicted proportions of hyper- vs hypoinflammatory subphenotypes in Asians.
- Poor agreement across six established classifiers, indicating model-specific variability.
- In the Asian cohort, Berlin-definition ARDS displayed higher inflammatory profiles than HFNC-ARDS, highlighting definitional heterogeneity.
Methodological Strengths
- International, prospective enrollment with broad biomarker profiling and sensitivity analyses including latent class analysis.
- Direct cross-ancestry comparison leveraging overlapping biomarkers between cohorts.
Limitations
- Only 10 biomarkers overlapped between sites, potentially contributing to intermodel discordance.
- Moderate sample size and inclusion of HFNC-ARDS may introduce heterogeneity.
Future Directions: Develop and validate unified, assay-agnostic classifiers across ancestries; test predictive enrichment for treatment responsiveness; standardize biomarker measurement platforms.