Daily Respiratory Research Analysis
Translational and clinical studies advanced respiratory medicine today: a mechanistic study identified macrophage-derived CCL18 as a driver and biomarker of checkpoint inhibitor pneumonitis, while pooled RCT data showed tezepelumab reduces infection-attributed asthma exacerbations. A prospective primary care cohort quantified RSV burden in older adults as substantial and comparable to influenza, informing vaccination policy.
Summary
Translational and clinical studies advanced respiratory medicine today: a mechanistic study identified macrophage-derived CCL18 as a driver and biomarker of checkpoint inhibitor pneumonitis, while pooled RCT data showed tezepelumab reduces infection-attributed asthma exacerbations. A prospective primary care cohort quantified RSV burden in older adults as substantial and comparable to influenza, informing vaccination policy.
Research Themes
- Immune-mediated lung injury mechanisms and biomarkers
- Biologic therapy reducing infection-triggered asthma exacerbations
- Respiratory syncytial virus burden in older adults and implications for vaccination
Selected Articles
1. Macrophage CCL18 Promotes Lung Inflammation in Checkpoint Inhibitor Pneumonitis.
Multi-omic profiling of BALF from patients with checkpoint inhibitor pneumonitis revealed expansion of pro-inflammatory alveolar macrophage subsets with marked upregulation of CCL18, which correlated with clinical severity. In vivo CCL18 overexpression in mice phenocopied human CIP with enhanced lung inflammation, implicating CCL18 as a causal mediator and potential biomarker/therapeutic target.
Impact: This study provides mechanistic and causal evidence linking macrophage-derived CCL18 to CIP pathogenesis, offering a measurable biomarker and a tractable target for intervention.
Clinical Implications: BALF CCL18 could aid CIP risk stratification and monitoring; therapeutics targeting CCL18 or its signaling may mitigate CIP without broadly suppressing antitumor immunity.
Key Findings
- CIP patients showed increased alveolar macrophages with multiple pro-inflammatory subsets by scRNA-seq and flow cytometry.
- CCL18 expression (transcript, cellular, and BALF protein) was elevated in CIP and associated with greater clinical severity.
- CCL18 overexpression in mice induced lung inflammation that phenocopied human CIP, including pro-inflammatory macrophage signatures.
Methodological Strengths
- Integrated multi-omic human BALF profiling (scRNA-seq, flow cytometry, ELISA) with external cohort validation
- In vivo functional modeling demonstrating causality of CCL18 in lung inflammation
Limitations
- Sample sizes and enrollment details are not fully specified; generalizability across tumor types requires confirmation
- Interventional blockade of CCL18 was not tested; murine overexpression may not recapitulate all human CIP features
Future Directions: Prospective studies validating BALF/serum CCL18 as a predictive biomarker and interventional trials targeting CCL18 signaling to prevent or treat CIP.
2. Effect of tezepelumab on asthma exacerbations co-occurring with infection-attributed acute respiratory illnesses.
Across pooled phase 2b/3 trials (n=1334), tezepelumab reduced asthma exacerbations co-occurring with respiratory illness-related AEs attributed to infections versus placebo (18.2% vs 28.6%; exposure-adjusted incidence difference −11.1). Reductions were consistent in patients with and without perennial allergy.
Impact: Post hoc pooled RCT evidence indicates that upstream TSLP blockade reduces infection-attributed exacerbations, a common trigger with high morbidity.
Clinical Implications: Tezepelumab may be prioritized in severe asthma patients with frequent infection-triggered exacerbations, supporting broader preventive benefits beyond eosinophilic pathways.
Key Findings
- Among 1334 patients, co-occurring infection-attributed exacerbations were lower with tezepelumab vs placebo (18.2% vs 28.6%; EAID −11.1).
- Effect sizes were similar in perennial allergy subgroups (EAID −11.6 with allergy; −10.2 without).
- Benefits were observed over 52 weeks of subcutaneous dosing every 4 weeks.
Methodological Strengths
- Pooled analysis of two large randomized, placebo-controlled trials with standardized definitions
- Stratified subgroup analyses by perennial allergy status
Limitations
- Post hoc analysis; co-occurrence relied on AE attribution without pathogen confirmation for all events
- Mechanisms of infection-related protection were not directly assessed
Future Directions: Prospective studies with pathogen-confirmed ARIs to define tezepelumab effects on specific infections and to elucidate TSLP–host defense interactions.
3. Clinical and Socioeconomic Burden of RSV Infections Among Older Adults in Primary Care: An International Prospective Cohort Study.
In a two-country prospective primary care cohort of adults ≥60 years (n=703), RSV accounted for 13.2% of ARIs with mean illness duration of 17 days, 38% repeat visits, and nontrivial costs (€78 healthcare; €280 societal). RSV clinical and socioeconomic burdens were comparable to influenza, and incidence in Dutch primary care was 10.3 per 1000 person-years.
Impact: Provides robust primary care evidence of RSV burden in older adults comparable to influenza, directly informing vaccine policy and prioritization.
Clinical Implications: Supports targeting older adults in RSV vaccination programs and anticipatory care planning in primary care during RSV seasons.
Key Findings
- RSV positivity was 13.2% among older adults with ARI; mean illness duration was 17 days with 38% repeat visits.
- Per-episode costs averaged €78 (healthcare) and €280 (societal); hospitalization occurred in 2%.
- RSV burden (clinical and socioeconomic) was comparable to influenza; incidence estimated at 10.3 per 1000 person-years.
Methodological Strengths
- Prospective multicenter primary care design across two countries and two seasons
- Standardized testing for RSV and influenza with repeated burden assessments (Days 1, 14, 30)
Limitations
- Relatively modest number of RSV-positive cases limits precision of subgroup estimates
- Primary care sampling may miss more severe cases and under/overestimate resource use
Future Directions: Evaluate vaccine effectiveness and cost-effectiveness in primary care, and define risk stratification tools to triage older adults during RSV seasons.