Weekly Respiratory Research Analysis
This week’s respiratory literature centers on prevention and mechanistic advances. A mechanistic study links IL‑4/IL‑13–driven epithelial ALDH2 downregulation to alcohol‑induced respiratory reactions in AERD and shows reversibility with dupilumab. Large pragmatic randomized trials support broader use of enhanced respiratory vaccines — high‑dose influenza and RSVpreF — in older adults, while infant and neonatal RSV immunoprophylaxis (nirsevimab, live or prefusion vaccines) show strong real‑world/
Summary
This week’s respiratory literature centers on prevention and mechanistic advances. A mechanistic study links IL‑4/IL‑13–driven epithelial ALDH2 downregulation to alcohol‑induced respiratory reactions in AERD and shows reversibility with dupilumab. Large pragmatic randomized trials support broader use of enhanced respiratory vaccines — high‑dose influenza and RSVpreF — in older adults, while infant and neonatal RSV immunoprophylaxis (nirsevimab, live or prefusion vaccines) show strong real‑world/early efficacy. Additional high‑impact work advances predictive platforms (nasal organoids) and identifies druggable fibrotic pathways (ARG1).
Selected Articles
1. Reduced aldehyde dehydrogenase 2 in respiratory tract associates with dysregulated alcohol metabolism and respiratory reactions in aspirin-exacerbated respiratory disease.
In a 600‑patient AERD cohort, alcohol‑induced upper and lower respiratory symptoms were common and associated with worse disease control and elevated eicosanoids. Respiratory tract ALDH2 expression was reduced in AERD; IL‑4/IL‑13 decreased ALDH2 in epithelial cultures and IL‑4Rα blockade with dupilumab increased nasal ALDH2 transcripts and improved alcohol‑triggered symptoms, supporting an acquired type‑2 inflammation–mediated ALDH2 deficiency driving acetaldehyde accumulation and mast cell activation.
Impact: Unifies clinical phenotype (alcohol triggers) with a mechanistic epithelial metabolic defect driven by type‑2 cytokines and demonstrates therapeutic reversibility with dupilumab, introducing ALDH2 as a potential biomarker and target for symptom control.
Clinical Implications: Counsel patients with AERD about alcohol triggers; consider that IL‑4/IL‑13–targeted therapy (e.g., dupilumab) may mitigate alcohol‑induced respiratory reactions and partially normalize epithelial ALDH2 expression. ALDH2 assessment could stratify susceptibility.
Key Findings
- Alcohol‑induced upper (79.6%) and lower (45.1%) respiratory symptoms were frequent in AERD and linked to worse sinus/asthma control and higher urinary eicosanoids.
- ALDH2 protein/transcripts in nasal tissues were reduced in AERD; IL‑4/IL‑13 suppressed ALDH2 in vitro and dupilumab increased nasal ALDH2 transcription in vivo concomitant with symptom improvement.
2. Live-Attenuated Intranasal RSV Vaccine in Infants and Toddlers.
A multicenter phase I/II randomized trial of a live‑attenuated intranasal RSV vaccine (RSVt) in 6–18 month olds showed robust immunogenicity: RSV‑naïve infants had substantially higher RSV A neutralizing GMTs after doses 1 and 2 versus placebo, with no unsolicited systemic adverse events within 30 minutes and an acceptable solicited reactogenicity profile. Findings support progression to efficacy trials targeting mucosal immunity and hospitalizations.
Impact: Directly addresses a longstanding gap by demonstrating immunogenicity and early safety of a mucosal live RSV vaccine in the target pediatric population, potentially enabling a deployable infant vaccine that induces mucosal immunity.
Clinical Implications: Supports advancement to phase III efficacy trials focusing on RSV hospitalization prevention, mucosal immunity durability, and deployment logistics for infant immunization programs.
Key Findings
- In RSV‑naïve infants, neutralizing GMTs post‑dose 1 and dose 2 were markedly higher with RSVt versus placebo (e.g., dose 2 GMTs: LD 142.0, HD 107.0 vs placebo 26.3).
- No unsolicited systemic adverse events within 30 minutes; solicited local/systemic reactions were common but acceptable across dose groups.
3. 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 pragmatic, registry‑linked randomized trial of adults ≥65 across three seasons, high‑dose inactivated influenza vaccine reduced influenza‑related hospitalizations compared with standard‑dose with consistent relative effectiveness in participants with and without pre‑existing atherosclerotic cardiovascular disease (ASCVD). No heterogeneity by ASCVD status was observed for respiratory or cardiovascular outcomes.
Impact: Provides large pragmatic randomized evidence to favor high‑dose influenza vaccination in older adults regardless of ASCVD, informing vaccination policy and simplifying prioritization across cardiopulmonary clinics.
Clinical Implications: Clinicians caring for adults ≥65 can preferentially offer high‑dose influenza vaccine to reduce influenza hospitalizations irrespective of ASCVD status; integration into routine geriatric and cardiology vaccination programs is reasonable.
Key Findings
- Relative vaccine effectiveness for influenza/pneumonia hospitalization favored high‑dose over standard dose with similar rVE in ASCVD and non‑ASCVD groups (no significant interaction).
- Influenza hospitalizations were substantially reduced (rVE ~43–46%) in both ASCVD strata; MACE outcomes showed small, non‑significant differences.