Daily Respiratory Research Analysis
Dynamic monitoring of pneumonia severity using a new machine-learning trend score outperformed existing models and generalized across international cohorts. Serum IgA biology emerged as a contributor to emphysema and airway disease via population cohorts and Mendelian randomization. A first-in-class sulfonium lipid nanoparticle enabled intranasal mRNA delivery and genome editing across key lung epithelial and immune cells in mice, opening a path for inhaled genetic therapies.
Summary
Dynamic monitoring of pneumonia severity using a new machine-learning trend score outperformed existing models and generalized across international cohorts. Serum IgA biology emerged as a contributor to emphysema and airway disease via population cohorts and Mendelian randomization. A first-in-class sulfonium lipid nanoparticle enabled intranasal mRNA delivery and genome editing across key lung epithelial and immune cells in mice, opening a path for inhaled genetic therapies.
Research Themes
- Dynamic risk stratification and prognosis in community-acquired pneumonia
- Humoral immunity (IgA) in emphysema and airway remodeling
- Intranasal mRNA delivery and genome editing in the lung
Selected Articles
1. Dynamically monitoring pneumonia severity scores to predict the prognosis in patients with community-acquired pneumonia: an international, multicenter cohort study.
A new trend-based algorithm (Mortality Vector Optimization) quantified changes in CURB-65/PSI between admission and 72 hours, improving in-hospital mortality prediction versus nine ML comparators and generalizing to two external datasets. The derived trend score strongly captured disease progression (HR ~2.5), supporting dynamic monitoring of treatment response in CAP.
Impact: Introduces a practical, externally validated method to dynamically track CAP severity and improve mortality prediction using familiar scores. This can reshape early treatment decisions and escalation strategies.
Clinical Implications: Embedding MVO-derived trend scores into electronic health records could enable real-time risk updates to guide ICU triage, antibiotic de-escalation/escalation, and response-adaptive care pathways during the first 72 hours.
Key Findings
- MVO outperformed nine established ML models for mortality prediction using PSI/CURB-65 dynamics (derivation AUC for PSI 0.825; external AUC up to 0.870).
- Trend score captured disease progression with strong associations to in-hospital mortality (HR 2.63 for CURB-65 trend; HR 2.50 for PSI trend).
- External validation across GOSSIS-1-eICU and SCRIPT CarpeDiem datasets demonstrated generalizability.
Methodological Strengths
- International, multicenter cohorts with predefined timepoints (admission and 72-hour reassessment).
- External validation on independent critical care datasets; discrimination and calibration assessed.
Limitations
- Observational design with potential residual confounding and practice variability.
- Prospective impact on clinical decision-making and outcomes not yet tested in randomized implementation studies.
Future Directions: Prospective, cluster-randomized evaluations of MVO-guided care pathways; integration with EHRs; extension to sepsis/viral pneumonia and incorporation of biomarkers and imaging.
2. Serum IgA isotypes are associated with percent emphysema, wall thickness and lung function decline.
In MESA (n=5,497), lower serum IgA was associated with higher CT percent emphysema, supported by Mendelian randomization. Higher galactose-deficient IgA1 correlated with airway wall thickening and accelerated decline in FEV1 and FEV1/FVC, with replication in SPIROMICS, implicating humoral immunity in emphysema and airway remodeling.
Impact: Links systemic IgA biology to structural lung disease using imaging, longitudinal function, and genetic instruments, suggesting a potentially modifiable immune pathway in emphysema.
Clinical Implications: IgA-related biomarkers could aid risk stratification for emphysema and airway disease; interventions that enhance mucosal IgA or reduce pathogenic Gd-IgA1 may be explored to modify disease progression.
Key Findings
- Lower serum IgA associated with greater CT-derived percent emphysema (β=-0.084; p=0.005), confirmed by Mendelian randomization (β=-0.79; p=0.011).
- Higher serum galactose-deficient IgA1 linked to increased airway wall thickness (β=0.0079; p=0.012) and accelerated decline in FEV1 and FEV1/FVC.
- Findings replicated across cohorts (SPIROMICS), implicating humoral immunity in emphysema pathogenesis and airway remodeling.
Methodological Strengths
- Large population-based cohort with CT phenotyping and spirometry, plus replication.
- Use of Mendelian randomization to strengthen causal inference.
Limitations
- Serum IgA may not fully reflect mucosal IgA; residual confounding possible.
- Effect sizes modest; interventional relevance requires testing.
Future Directions: Mechanistic studies of mucosal IgA and Gd-IgA1 in lung tissue; trials testing strategies to augment protective IgA or reduce Gd-IgA1; integration with microbiome and infection phenotypes.
3. Sulfonium lipid nanoparticles for intranasal mRNA delivery to lung epithelial and immune cells.
A first-in-class sulfonium lipid nanoparticle enabled intranasal delivery of mRNA to club and ciliated epithelial cells and macrophages in mice, supporting applications from bioluminescence imaging to CRISPR genome editing and cytokine delivery. No sustained toxicity was observed, suggesting a safe alternative to amine-based pulmonary lipids.
Impact: Demonstrates a new chemical class for pulmonary mRNA delivery with in vivo efficacy across multiple lung cell types and payloads, addressing a key translational bottleneck for inhaled genetic therapies.
Clinical Implications: If translated, sLNPs could support inhaled mRNA therapeutics for cystic fibrosis, influenza/RSV prophylaxis, gene editing of monogenic lung diseases, and localized immunomodulation with reduced systemic exposure.
Key Findings
- Sulfonium lipid nanoparticles achieved efficient intranasal mRNA delivery to club cells, ciliated epithelial cells, and macrophages in vivo.
- Enabled functional payloads including CRISPR-Cas9 mRNA/sgRNA for genome editing and cytokine mRNA for immunomodulation.
- Demonstrated safety in adult mice without sustained local or systemic toxicity, offering a non-amine alternative for pulmonary delivery.
Methodological Strengths
- In vivo demonstration across multiple lung cell types with diverse mRNA cargos.
- Safety assessment indicating no sustained inflammation or tissue damage.
Limitations
- Preclinical murine study; human translatability, dose scaling, and durability remain to be established.
- Long-term immunogenicity and repeated dosing effects were not fully characterized.
Future Directions: Optimization of sLNP chemistry and nebulization for human airways, disease-model testing (e.g., CFTR correction), GLP toxicology, and first-in-human studies for inhaled mRNA therapeutics.