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.
Checkpoint inhibitor pneumonitis (CIP) is a highly morbid complication of immune checkpoint immunotherapy, characterized by acute lung injury leading, in severe cases, to hypoxic respiratory failure and death. CIP incidence in lung cancer is high (10-15%). Yet, the pathophysiology of CIP is poorly understood. To investigate the mechanisms underlying alveolar inflammation in patients with CIP, human bronchoalveolar fluid (BALF) samples from control and CIP patients were analyzed using flow cytometry, single cell RNA sequenc
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.
BACKGROUND: Tezepelumab, a human monoclonal antibody, blocks the activity of thymic stromal lymphopoietin. In the phase 2b PATHWAY (NCT02054130) and phase 3 NAVIGATOR (NCT03347279) studies, tezepelumab reduced exacerbations and improved lung function, asthma control, and health-related quality of life vs placebo in patients with severe, uncontrolled asthma. OBJECTIVE: To evaluate the incidence of asthma exacerbations co-occurring with documented acute respiratory illnesses attributed to infections. METHODS: Patients were rando
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.
INTRODUCTION: Respiratory syncytial virus (RSV) is increasingly recognized as an important cause of acute respiratory infections (ARI) in older adults. However, primary care data on RSV infections are scarce. METHODS: We conducted a prospective cohort study over two winter seasons (2022-2023 and 2023-2024) in Italy and the Netherlands (NCT06318936). Older adults (≥ 60 years) presenting to primary care with ARI were tested for RSV and influenza. Clinical and socioeconomic burden was assessed through questionnaires on Days 1, 14, and 30. In secondary analyses, we compared between RSV- and influenza-positive patients and estimated RSV-ARI incidence in Dutch primary care. RESULTS: Of 703 older adults tested, 93 (13.2%) were RSV-positive and 100 (14.2%) influenza-positive. In RSV patients (mean age: 76 years [SD: 8], 63% ≥ 1 comorbidity), mean illness duration was 17 days (SD: 10). Repeat primary care visits occurred in 38% (33/87), emergency department referral in 5% (4/88), and hospitalization in 2% (2/88) of RSV patients. The mean costs per RSV episode were €78.1 (95%CI: 74.4-81.8) and €279.7 (95%CI: 245.5-318.2) from a healthcare system and societal perspective, respectively. The annual RSV-ARI incidence rate was 10.3 episodes per 1000 person-years. RSV patients were significantly older, and had less often fever, muscle pain, and fatigue than influenza patients, but clinical and socioeconomic burdens were comparable. CONCLUSIONS: This prospective study is the first sufficiently large to demonstrate that the primary care burden of RSV infections among older adults is substantial and comparable with influenza. These findings are highly relevant for informing public health decisions on novel RSV vaccines.