Daily Respiratory Research Analysis
Analyzed 155 papers and selected 3 impactful papers.
Summary
Analyzed 155 papers and selected 3 impactful articles.
Selected Articles
1. Integrated human and mouse single-cell profiling reveals immune-stromal niche driving silicosis.
Human lavage scRNAseq revealed CCL2-high monocyte-like macrophages differentiating into IL1B-high inflammatory and SPP1-high pre-fibrotic states. An integrated site-specific mouse model and cell–cell communication analysis identified Sfrp1-high/Spp1-high fibroblasts and reprogrammed AT2 cells engaged in extensive crosstalk with macrophages, nominating targetable immune–stromal interactions in silicosis.
Impact: This study elucidates a previously undefined immune–stromal niche in silicosis across human and mouse, uncovering macrophage-fibroblast circuits and pre-fibrotic states that nominate actionable targets.
Clinical Implications: While preclinical, the identification of CCL2- and SPP1-centered macrophage–fibroblast crosstalk suggests therapeutic avenues (e.g., CCL2/CCR2, SPP1 pathway blockade) and biomarkers to stratify patients for anti-fibrotic interventions.
Key Findings
- Human scRNAseq identified expansion of CCL2-high monocyte-like macrophages differentiating into IL1B-high inflammatory and SPP1-high pre-fibrotic subsets.
- SPP1-high macrophages were enriched for tissue remodeling, oxidative stress, and biomineralization gene programs.
- A site-specific silicosis mouse model plus scRNAseq uncovered Sfrp1-high/Spp1-high fibroblast subsets and reprogrammed AT2 cells engaged in extensive macrophage–stromal crosstalk.
Methodological Strengths
- Integrated human and mouse scRNAseq with cell–cell communication modeling
- Novel site-specific silicosis mouse model via mini-bronchoscopy enabling spatially targeted injury
Limitations
- Human sample size and cohort characteristics are not specified within the abstract, limiting generalizability assessment
- Predicted macrophage–stromal interactions require functional validation for therapeutic targeting
Future Directions: Functionally validate CCL2/SPP1-axis interactions, test targeted inhibitors in vivo, and develop biomarker-driven stratification for early-phase anti-fibrotic trials in silicosis.
Silicosis is an inflammation-driven pulmonary fibrosis caused by occupational inhalation of silica particles. Macrophages are crucial in silicosis pathology, yet their interaction with stromal cells in orchestrating fibrosis progression remains poorly understood. Single-cell RNA sequencing (scRNAseq) of whole-lung lavages from silicosis patients identified the expansion of an intermediate CCL2-hi monocyte-like macrophage (MLM) cluster that further differentiated into inflammatory IL1B-hi and pre-fibrotic SPP1-hi (osteopontin) subsets. SPP1-hi MLMs showed enrichment for tissue remodelling (SPP1, CHI3L1, MMP14, COL6A1), oxidative stress (GCLC, TXN, PRDX1), and bio-mineralisation genes (GLA, CA2, CTSK). To explore immune-stromal dynamics, we developed a site-specific silicosis mouse model via mini-bronchoscopy. Mouse scRNAseq analysis and cell-cell communication modelling identified novel neutrophil subsets, reprogrammed alveolar type 2 epithelial cells, and two Sfrp1-hi/Spp1-hi fibroblast subsets involved in extensive crosstalk with MLMs. These data identify key components of the silicotic niche and predict targetable interactions within the immune-stromal axis for ameliorating disease.
2. High-Dose vs Standard-Dose Influenza Vaccine in Older Adults With Diabetes: A Secondary Analysis of the DANFLU-2 Randomized Clinical Trial.
In a prespecified secondary analysis of a large pragmatic randomized trial (n=332,438), high-dose inactivated influenza vaccine reduced cardiorespiratory, cardiovascular, and influenza hospitalizations compared with standard-dose in adults ≥65 years. Benefits were consistent regardless of diabetes status, with a signal of greater benefit for cardiorespiratory hospitalization among those with diabetes duration >5 years.
Impact: This trial-scale analysis provides robust, policy-relevant evidence favoring high-dose influenza vaccination to reduce serious respiratory and cardiovascular hospitalizations in older adults, including those with diabetes.
Clinical Implications: Consider preferential use of high-dose influenza vaccine for adults ≥65 years, irrespective of diabetes, and especially for those with longer diabetes duration (>5 years) to reduce cardiorespiratory hospitalizations.
Key Findings
- Among 332,438 adults ≥65 years, high-dose vaccine reduced cardiorespiratory, cardiovascular, and influenza hospitalizations versus standard-dose.
- Relative vaccine effectiveness against cardiorespiratory hospitalization was similar with and without diabetes (7.4% vs 5.3%; interaction P=0.69).
- Diabetes duration modified effect: >5 years duration showed a 20.4% rVE (95% CI, 5.3%-33.1%) for cardiorespiratory hospitalization; ≤5 years showed no benefit.
- Benefits were consistent across outcomes with no significant interaction by diabetes status for influenza hospitalization (interaction P=0.87).
Methodological Strengths
- Individually randomized, nationwide pragmatic design with registry-based outcome ascertainment
- Very large sample size enabling precise subgroup analyses, including diabetes duration
Limitations
- Open-label design; potential for behavioral differences despite hard registry outcomes
- Secondary analysis; some interaction findings (e.g., diabetes duration) warrant prospective confirmation
Future Directions: Prospective evaluation of dose strategies across multimorbidity and frailty strata, and cost-effectiveness analyses to inform guideline updates.
IMPORTANCE: Influenza infection poses a substantial risk of severe complications, particularly in older adults and high-risk populations, such as individuals with diabetes. The high-dose inactivated influenza vaccine (HD-IIV) has demonstrated superior efficacy against influenza infection compared with the standard-dose inactivated influenza vaccine (SD-IIV) among adults 65 years or older. However, there is limited evidence on its effectiveness in preventing severe respiratory and cardiovascular outcomes in individuals with diabetes. OBJECTIVE: To investigate the relative vaccine effectiveness (rVE) of HD-IIV vs SD-IIV against severe respiratory and cardiovascular outcomes according to diabetes status and across diabetes subgroups. DESIGN, SETTING, AND PARTICIPANTS: This was a prespecified secondary analysis of DANFLU-2, a pragmatic, open-label, individually randomized clinical trial conducted in Denmark during the 2022/2023 to 2024/2025 influenza seasons. Adults 65 years or older were eligible for inclusion regardless of comorbidities. Data were obtained from nationwide health registries and analyzed from June to October 2025. INTERVENTIONS: Participants were randomly allocated 1:1 to receive HD-IIV or SD-IIV. MAIN OUTCOMES AND MEASURES: Outcomes included respiratory and cardiovascular hospitalizations. The potential effect modification by diabetes status and across diabetes subgroups was tested. RESULTS: Among 332 438 participants (mean [SD] age, 73.7 [5.8] years; 161 538 female individuals [48.6%]), 43 881 (13.2%) had diabetes. Overall, HD-IIV compared with SD-IIV was associated with reduced cardiorespiratory hospitalization, cardiovascular hospitalization, and influenza hospitalization. Effect estimates were similar for participants with and without diabetes for cardiorespiratory hospitalization (diabetes: rVE, 7.4%; 95% CI, -2.5% to 16.3%; no diabetes: rVE, 5.3%; 95% CI, 0.4%-10.0%; interaction P = .69), cardiovascular hospitalization (diabetes: rVE, 12.0%; 95% CI, -0.9% to 23.3%; no diabetes: rVE, 6.0%; 95% CI, -0.4% to 12.0%; interaction P = .38), and influenza hospitalization (diabetes: rVE, 41.6%; 95% CI, 5.0%-64.7%, vs no diabetes: rVE, 44.3%; 95% CI, 25.3%-58.7%; interaction P = .87). Duration of diabetes appeared to modify the effect of HD-IIV vs SD-IIV for cardiorespiratory hospitalization, with suggested benefit of HD-IIV in participants with diabetes duration longer than 5 years (rVE, 20.4%; 95% CI, 5.3%-33.1%), but not in those with shorter duration (rVE, -0.4%; 95% CI, -13.8% to 11.5%; interaction P = .03). CONCLUSIONS AND RELEVANCE: The trial results suggest that, among adults 65 years or older, HD-IIV provided consistent benefit for cardiorespiratory, cardiovascular, and influenza hospitalizations compared with SD-IIV, regardless of diabetes status. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05517174.
3. Budesonide-formoterol versus terbutaline reliever in adults with asthma using maintenance inhaled corticosteroids in New Zealand (INFORM ASTHMA): an open-label, parallel-group, randomised, controlled, phase 4 trial.
In adults with asthma on maintenance ICS and FeNO ≥25 ppb, as-needed budesonide–formoterol reduced FeNO by 18.5% versus terbutaline after 26 weeks, with similar adverse event rates and no deaths. This supports budesonide–formoterol reliever as a safe, anti-inflammatory alternative to SABA reliever therapy.
Impact: This registered, phase 4 RCT fills a key evidence gap for reliever choice in adults on maintenance ICS and demonstrates anti-inflammatory benefits measured by FeNO.
Clinical Implications: For adults using maintenance ICS with evidence of type 2 inflammation, as-needed budesonide–formoterol can be considered over SABA reliever to reduce airway inflammation; implementation may extend to broader practice pending exacerbation and patient-reported outcomes.
Key Findings
- As-needed budesonide–formoterol reduced FeNO by 18.5% versus terbutaline at 26 weeks (p=0.024).
- Adverse event rates were similar between groups; no deaths occurred.
- Trial enrolled adults with FeNO ≥25 ppb on maintenance ICS, addressing a population lacking prior RCT evidence for reliever choice.
Methodological Strengths
- Randomised, controlled phase 4 design with ITT analysis and trial registration
- Stratified randomisation and predefined biomarker endpoint (FeNO)
Limitations
- Open-label design may introduce performance bias
- Primary endpoint was FeNO (surrogate) rather than exacerbations or clinical outcomes; sample size modest
Future Directions: Conduct blinded, larger RCTs powered for exacerbations and patient-reported outcomes, evaluate diverse ICS doses and phenotypes, and assess cost-effectiveness and implementation in primary care.
BACKGROUND: Recommendations for the use of inhaled corticosteroid-formoterol reliever-based regimens are limited by the absence of randomised controlled trials (RCTs) in patients with asthma using maintenance inhaled corticosteroids, and scarce evidence for the effect on type 2 airway inflammation. We aimed to examine the clinical efficacy and safety of maintenance inhaled corticosteroids plus budesonide-formoterol reliever or terbutaline reliever in patients with mild-to-moderate asthma. METHODS: This open-label, parallel-group, randomised, controlled, phase 4 trial was conducted at Wellington Hospital and two community-based primary care facilities in New Zealand. Eligible participants were aged 16-75 years, had a self-reported doctor's diagnosis of asthma, were using reliever only therapy or maintenance inhaled corticosteroids with short-acting β2-agonist reliever therapy, and were registered with a general practitioner. Participants had to have reported mean reliever use on two or more occasions per week in the 12 weeks before enrolment and had evidence of airway inflammation (FeNO ≥25 parts per billion [ppb]) at screening. Participants were randomly assigned (1:1) to budesonide-formoterol (budesonide 200 μg and formoterol 6 μg) reliever or terbutaline 250 μg reliever therapy using a computer-generated sequence in block sizes of four and six, stratified by region, baseline inhaled corticosteroids maintenance dose, and history of severe asthma exacerbation in the previous 12 months. All participants received maintenance budesonide 200 μg. During a 26-week treatment period, participants attended visits at weeks 0 (screening and randomisation), 13, and 26. The primary outcome was FeNO at week 26, measured in the intention-to-treat (ITT) population. This trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12622001304729 (completed). FINDINGS: Between March 28, 2023, and Aug 27, 2024, 290 participants were assessed for eligibility, 109 were ineligible, and 181 were randomly assigned to budesonide-formoterol (n=93) or terbutaline reliever therapy (n=88; ITT population). Participants had a mean age of 33·91 years (SD 15·54). 119 (66%) of 181 participants were female and 62 (34%) were male. Geometric mean FeNO was 62·18 ppb (SD 1·86) at baseline and 39·65 ppb (2·12) at week 26, for the budesonide-formoterol group and 68·03 ppb (1·97) at baseline and 52·98 ppb (2·27) at week 26 for the terbutaline group. Budesonide-formoterol reliever therapy resulted in a mean reduction in geometric mean FeNO of 18·50% (95% CI 2·72-31·73; p=0·024) at week 26 compared with terbutaline reliever therapy. 77 (83%) of 93 participants in the budesonide-formoterol group versus 69 (78%) of 88 in the terbutaline group had at least one adverse event (relative risk 1·06 [95% CI 0·91-1·22]; p=0·46). There were no deaths in the study. INTERPRETATION: Budesonide-formoterol reliever therapy resulted in a reduction in FeNO compared with terbutaline reliever in adults with asthma using maintenance inhaled corticosteroids. Budesonide-formoterol reliever is a safe and effective alternative to short-acting β2-agonist reliever therapy for adults using maintenance inhaled corticosteroids. FUNDING: AstraZeneca.