Daily Respiratory Research Analysis
Analyzed 148 papers and selected 3 impactful papers.
Summary
Analyzed 148 papers and selected 3 impactful articles.
Selected Articles
1. Deupirfenidone Compared with Pirfenidone and Placebo in Idiopathic Pulmonary Fibrosis (ELEVATE-IPF): a Phase 2b Randomized Placebo-Controlled Trial.
In this phase 2b, randomized, placebo- and active-controlled trial in 257 IPF patients, deupirfenidone reduced the 26-week decline in FVC compared with placebo, with the 825 mg TID dose showing a statistically significant adjusted mean difference (~91 mL). The safety profile was acceptable and predominantly gastrointestinal, supporting further development.
Impact: This is a rigorously conducted randomized study suggesting a new antifibrotic option that slows physiological decline in IPF over 26 weeks, with a differentiated pharmacokinetic rationale.
Clinical Implications: If confirmed in larger and longer trials, deupirfenidone could expand antifibrotic options for IPF and may offer comparable efficacy with acceptable tolerability. Clinicians should monitor gastrointestinal adverse events and consider FVC trajectory endpoints in shared decision-making.
Key Findings
- Randomized 1:1:1:1 comparison showed reduced 26-week FVC decline with deupirfenidone versus placebo; the 825 mg TID arm had an adjusted mean difference of 91 mL (P = .02).
- Bayesian analysis supported a high posterior probability (0.985) favoring deupirfenidone over placebo.
- Gastrointestinal adverse events were the most common and overall tolerability was acceptable across active arms.
Methodological Strengths
- Randomized, placebo- and active-controlled, multicenter phase 2b design with both Bayesian and frequentist analyses.
- Predefined physiologic endpoint (FVC change) aligned with IPF trial standards.
Limitations
- Short 26-week follow-up limits assessment of long-term efficacy, mortality, and exacerbations.
- Sample size and duration may be underpowered for safety signals beyond common gastrointestinal events.
Future Directions: Proceed to phase 3 trials with longer follow-up to test effects on mortality, acute exacerbations, and quality of life; explore exposure–response and tolerability optimization.
RATIONALE: Deupirfenidone is a strategically deuterated form of pirfenidone that retains pharmacodynamic activity but has a differentiated pharmacokinetic profile that may enable improved efficacy and favorable tolerability in patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVE: To evaluate the efficacy and safety of deupirfenidone compared with placebo and pirfenidone in patients with IPF. METHODS: Patients were randomized 1:1:1:1 to deupirfenidone 550 mg TID, deupirfenidone 825 mg TID, pirfenidone 801 mg TID or placebo. The primary endpoint was the rate of change in forced vital capacity (FVC) for the combined arms of deupirfenidone versus placebo at 26 weeks. The primary and secondary analyses used Bayesian and frequentist approaches, respectively. MEASUREMENTS AND MAIN RESULTS: 257 patients with IPF were randomized and the proportion on treatment at end of study was 80.0%, 68.3%, 64.6%, and 78.1% for the placebo, pirfenidone, deupirfenidone 550 mg, and deupirfenidone 825 mg arms, respectively. Posterior mean change in FVC for placebo was -110.71 mL (95% credible interval (CI), -148.75, -70.98) and for the combined deupirfenidone arms was -48.42 mL (95% CI, -87.66, -9.04) with a posterior mean difference of 62.29 mL (95% CI l, -6.13, 115.73; posterior probability, 0.985). Using a frequentist approach, the adjusted mean change in FVC for the placebo arm was -112.5 mL (95% CI, -167.2, -57.8) and for the deupirfenidone 825 mg arm was -21.5 mL (95% CI, -78.2, 35.1); the adjusted mean difference was 91.0 mL (95% CI, 12.2, 169.7; P = .02). The most common adverse events for each active treatment arm were gastrointestinal. CONCLUSIONS: In patients with IPF, treatment with deupirfenidone slowed lung disease progression over 26 weeks. TRIAL REGISTRATION: Clinicaltrials.gov number NCT05321420. ELEVATE IPF was a phase 2 b trial that studied the safety, tolerability, and effectiveness of the investigational drug deupirfenidone 550 mg TID (three times daily) and deupirfenidone 825 mg TID, compared to an approved antifibrotic drug, pirfenidone 801 mg TID, and placebo in patients living with idiopathic pulmonary fibrosis. The rate of decline in lung function measured by forced vital capacity at 26 weeks was significantly less for deupirfenidone 825 mg TID compared to placebo and was similar to the natural decline in lung function seen in healthy older adults. Deupirfenidone was also generally safe and well tolerated. These results support the continued development of deupirfenidone in IPF.
2. Infant RSV infection disrupts β2 adrenergic airway relaxation via epithelial CXCL11.
Across infant human tissue models and mouse validation, epithelial CXCL11 emerged as the dominant cytokine induced by RSV, acting via ACKR3 on airway smooth muscle to desensitize β2AR through phosphorylation, internalization, and degradation. Pharmacologic or genetic disruption of the CXCL11–ACKR3 pathway restored β2-agonist responsiveness, including when exposed to nasopharyngeal aspirates from severe bronchiolitis.
Impact: This study provides a unifying mechanism for β2-agonist failure in infant RSV bronchiolitis and identifies a druggable axis (CXCL11–ACKR3) with immediate translational potential.
Clinical Implications: Explains poor bronchodilator response in infant RSV and supports testing CXCL11/ACKR3 blockade to restore β2-agonist efficacy; may guide biomarker-driven trials using CXCL11 levels.
Key Findings
- RSV-infected infant airway epithelium secreted CXCL11, which via ACKR3 drove β2AR phosphorylation, internalization, and degradation in airway smooth muscle.
- CXCL11–ACKR3 signaling was necessary and sufficient for β2AR dysfunction (genetic variation, blockade, and rescue experiments).
- Blocking CXCL11 or ACKR3 restored β2-agonist responsiveness in infant PCLS exposed to RSV or severe bronchiolitis nasopharyngeal aspirates.
Methodological Strengths
- Use of complementary human infant tissue models (PCLS, epithelial ALI), mouse models, and validation with clinical nasopharyngeal aspirates.
- Multi-omic and functional assays (cytokine profiling, bulk RNA-seq, receptor function) to establish causality.
Limitations
- Preclinical nature; clinical efficacy of CXCL11/ACKR3 inhibitors remains to be tested.
- Sample sizes per experiment and patient heterogeneity details are not fully delineated in the abstract.
Future Directions: Early-phase clinical trials of ACKR3 or CXCL11 blockade in severe infant RSV bronchiolitis; development of assays to quantify airway CXCL11 and stratify responders.
RATIONALE: Airflow obstruction unresponsive to β2 adrenergic receptor (β2AR) agonists is a key feature of infant respiratory syncytial virus (RSV) bronchiolitis. The underlying mechanisms remain poorly understood, and effective treatment is lacking. OBJECTIVES: To investigate whether and how infant RSV infection affects β2AR signaling in airway smooth muscle cells (ASMCs). METHODS: We established complementary human and mouse models of RSV infection using infant (0-18 months) precision-cut lung slices (PCLSs), neonatal epithelial air-liquid interface (ALI) culture, and mouse pups to assess β2AR-mediated ASMC relaxation. Cytokine profiling was performed using conditioned medium (CM) from RSV-infected neonatal ALI culture. Infant ASMCs treated with CM were subjected to bulk RNA sequencing and β2AR expression and function assays. Findings were validated with nasopharyngeal aspirates (NPA) from infants with severe bronchiolitis. MEASUREMENTS AND MAIN RESULTS: RSV selectively targeted infant bronchial epithelium, inducing cytokine secretion that impaired β2AR-mediated ASMC relaxation. CXCL11 was the most upregulated epithelial cytokine and signaled to infant ASMCs through ACKR3, a β-Arrestin-poised receptor that interacted with β2AR to promote its phosphorylation, internalization, and degradation. Using mouse strains with genetic variation in Cxcl11, along with ACKR3 blockade and CXCL11 rescue assays, we demonstrated that CXCL11-ACKR3 signaling was both necessary and sufficient for β2AR dysfunction. Moreover, blockade of CXCL11 or ACKR3 restored β2AR responsiveness in infant PCLSs exposed to RSV or NPA from severe RSV bronchiolitis. CONCLUSIONS: Infant RSV bronchiolitis exploits CXCL11-ACKR3 signaling to desensitize β2AR in ASMCs. Targeting this pathway may improve β2AR agonist efficacy in severe RSV bronchiolitis.
3. Epidemiology, ventilation management, and clinical outcomes in children (PRoVENT-PED): first results from the 10-year, investigator-initiated, international, multicentre, prospective cohort study.
In 1427 invasively ventilated children across 83 ICUs in 34 countries, 28-day ICU mortality was 14%, higher in PARDS (27%) than non-PARDS (12%). Ventilation practices varied by age and PARDS status, and only PEEP, driving pressure, and FiO2 emerged as modifiable factors associated with outcomes.
Impact: This large, registered, international pediatric cohort delineates age- and syndrome-specific ventilation practices and identifies PEEP, driving pressure, and FiO2 as key modifiable factors linked to mortality, guiding future interventional trials.
Clinical Implications: Prioritize monitoring and optimization of PEEP, driving pressure, and FiO2 in pediatric ventilation strategies, particularly in PARDS, and consider age-specific tailoring of ventilator settings.
Key Findings
- Among 1427 children, overall 28-day ICU mortality was 14%, lowest in neonates (3%) and higher in PARDS (27%) versus non-PARDS (12%).
- Ventilator management varied with age and PARDS status; younger age and PARDS were associated with higher airway pressures.
- Only PEEP, driving pressure (ΔP), and FiO2 were identified as modifiable ventilation factors associated with outcomes.
Methodological Strengths
- International, multicentre, prospective cohort with preregistration (NCT06220825).
- Standardized data capture across 83 ICUs in 34 countries with predefined age strata.
Limitations
- Observational design limits causal inference and residual confounding may persist.
- Practice variability across ICUs and the 28-day horizon may affect generalizability.
Future Directions: Design interventional pediatric ventilation trials targeting PEEP and driving pressure thresholds, and validate age-specific protocols to reduce mortality.
BACKGROUND: Evidence supporting lung-protective ventilation in children overwhelmingly stems from adult trials. This study aimed to assess the epidemiology, ventilation management, and outcomes across predefined age groups of invasively ventilated critically ill children with or without paediatric acute respiratory distress syndrome (PARDS), and to identify potentially modifiable factors associated with outcome. METHODS: This 10-year, investigator-initiated, international, multicentre, observational prospective cohort study was conducted in 83 ICUs across 34 countries worldwide. Paediatric intensive care units were invited to participate in a registry. This phase of the study enrolled children (younger than 18 years) admitted to a participating centre who received invasive ventilation for at least 12 h. Preterm infants of a postconceptional age younger than 40 weeks and those receiving extracorporeal membrane oxygenation were excluded from participation. All data collected, including patient demographics, baseline characteristics, and ventilation data, were part of standard clinical care and retrieved from medical records. The primary outcome was 28-day intensive care unit (ICU) mortality. This study is registered at ClinicalTrials.gov (NCT06220825), the first phase of the study is completed, subsequent phases on different topics are currently running. FINDINGS: 1427 children (median age 24 months [IQR 7-96]; 799 [56%] were male and 628 [44%] were female) were enrolled between April 1, and June 30, 2024, and Oct 1, and Dec 31, 2024. PARDS was identified in 164 (11%) of 1427 children and occurred most frequently in preschool-aged children (aged 3 years to younger than 6 years). Ventilator management varied by age and PARDS status; decreased age and the presence of PARDS were associated with exposure to high airway pressures. 28-day ICU mortality was 14% (201 of 1427 children), and it was lowest in neonates (3 [3%] of 112 children) and higher in patients with PARDS than those without PARDS (44 [27%] of 164 vs 157 [12%] of 1263). Positive end-expiratory pressure (PEEP), driving pressure (ΔP) and fractional concentration of oxygen (FiO INTERPRETATION: Ventilation management in children varies substantially by age and PARDS status. Among potentially modifiable ventilation factors, only PEEP, ΔP, and FiO FUNDING: Amsterdam University Medical Centre and University Medical Centre Groningen.