Chest最新文献

Background: Black and Hispanic people with cystic fibrosis (PwCF) experience worse health outcomes. Health disparities are exacerbated by clinical research that does not adequately represent the diversity of the CF population.

Research questions: How do Black/African American and Hispanic/Latino(a) PwCF perceive clinical research? What are the barriers and facilitators to participation in research? Are there viable solutions to improve inclusion?

Study design and methods: Semi-structured, individual interviews were conducted with PwCF aged ≥18 years who identify as Black/African American race and/or Hispanic/Latino(a) ethnicity. Participants were recruited from six geographically diverse CF centers and through CF Foundation Community Voice, a CF community partner organization. The interview guide was created by a committee that included minoritized PwCF, research coordinators, and physician-scientists. Thematic analysis with inductive and deductive coding was used to analyze interview transcripts.

Results: Twenty PwCF were interviewed from 2024 to 2025. Drawing from a race-conscious adaptation of the Behavioral Model for Vulnerable Populations, we used domains of predisposing, need-based, and healthcare environment factors, as well as emergent themes relating to information and support needs. Participants discussed barriers to research participation that included narrow eligibility criteria (e.g., genotype requirements, health status) and logistical challenges such as time and cost. PwCF described a sense of isolation as persons of color with CF, which impacted sense of trust in CF care and research studies. They highlighted that racialized experiences, especially doubt surrounding their CF diagnosis, significantly impact willingness to participate. Solutions center around providing community support to address feelings of isolation and information needs to provide transparency about study design and intent.

Interpretation: Participation in clinical research is strongly influenced by an interplay of social, cultural, health, and systemic factors. Solutions to improve inclusion in trials center the needs of marginalized communities across all phases of study design and implementation.

Background: The ACCESS randomized double-blind controlled trial in hospitalized adults with community-acquired pneumonia (CAP) showed that adding clarithromycin to standard-of-care therapy accelerated clinical recovery within the first 72 hours after the commencement of treatment and reduced progression to organ dysfunction.

Research question: Does clarithromycin treatment modulate the circulating inflammatory protein profile in CAP, and can inflammatory endotypes identify patient subgroups with distinct clinical responses?

Study design and methods: Serum samples obtained from ACCESS trial patients at baseline and 72 hours were profiled using the Olink Target 96 Inflammation panel. Patients were grouped by treatment arm and by achievement of the trial's composite primary endpoint. After quality control, 70 proteins from 394 paired samples across 197 patients were analyzed to assess differential expression within and between groups over time, evaluate associations with clinical outcomes, and identify immune endotypes using unsupervised clustering.

Results: IL6 was selectively downregulated on day 4 in the clarithromycin arm, whereas IFN-γ, CXCL9, CXCL10, and SCF decreased over time across both treatment arms, consistent with resolution of inflammation. Among patients achieving the primary endpoint, IL6, CXCL9, CXCL10, and IFN-γ were suppressed only in clarithromycin-treated individuals. Clustering consistently identified two inflammatory endotypes with comparable SOFA, but distinct RSS scores. The endotype with lower RSS demonstrated higher IFN-γ and globally elevated inflammatory protein expression; in that endotype 90-day mortality was decreased with clarithromycin treatment.

Interpretation: Clarithromycin exerts measurable immunomodulatory effects in CAP, characterized by attenuation of pro-inflammatory cytokines, particularly IL6. The identification of distinct inflammatory endotypes suggests biological heterogeneity in CAP and supports future investigation of endotype-guided approaches to identify patients most likely to benefit from immunomodulatory therapies.

Clinical trial registration: ClinicalTrials.gov NCT04724044, EudraCT 2020-004452-15.

Background: Airway secretion retention is common in patients with acute respiratory failure (ARF), particularly in those requiring noninvasive respiratory support (NIRS). High-frequency chest wall oscillation (HFCWO) may improve airway clearance but critical care evidence remains limited.

Research question: Does adding HFCWO to standard care improve clinical outcomes in patients with bronchial hypersecretion and ARF requiring NIRS?

Study design and methods: We conducted a single-center randomized controlled trial in a RICU. Patients with ARF requiring NIRS, including high-flow nasal cannula (HFNC) and/or noninvasive ventilation (NIV), bronchial hypersecretion, and ineffective cough (peak cough expiratory flow <270 L/min) were randomized 1:1 to HFCWO plus standard care or standard care alone. The primary endpoint was therapeutic bronchoscopy. Secondary endpoints included hospital length of stay (LOS), RICU-LOS, NIRS duration, endotracheal intubation and mortality. Outcomes were analyzed using unadjusted and adjusted models accounting for age, sex, and main cause of hospitalization.

Results: Eighty-eight patients were enrolled (44 HFCWO, 44 control), with comparable baseline characteristics. Bronchoscopy was required in 6 patients (13.6%) versus 14 (31.8%) (unadjusted p=0.042); after adjustment the association did not retain statistical significance (adjusted OR 0.336, 95% CI 0.111-1.021; p=0.055). Secondary outcomes, analyzed without correction for multiple testing, are exploratory. Hospital stay (12 [10-15.5] vs 16.5 [13-21] days) and RICU stay (8 [7-10.5] vs 12 [9-17] days) were shorter, with adjusted reductions of 4.5 and 3.6 days. HFNC duration was shorter (6 [4-8] vs 9.5 [6-11.5] days) and remained significant after adjustment, whereas the reduction in NIV duration did not (adjusted p=0.166). No patient required intubation and mortality did not differ.

Interpretation: In this exploratory trial, HFCWO did not significantly reduce the need for therapeutic bronchoscopy after adjustment. Associated reductions in LOS and HFNC duration are hypothesis-generating and require confirmation in adequately powered multicenter trials.

Clinical trial registration: ClinicalTrials.gov: NCT05751707; Tuscany Ethics Committee (Protocol: 21987-10/17/2022).

Background: Heterozygous gain-of-function (GoF) variants in IFIH1 are associated with rare autoinflammatory diseases characterized by heightened interferons-stimulated gene (ISG) signatures. These include Aicardi-Goutières syndrome, presenting with slowly progressive spastic paraparesis of the lower limbs, intracerebral calcifications, and neuroinflammation, and Singleton-Merten syndrome, defined by tooth loss, bone demineralization, and vascular calcification.

Research question: Do rare IFIH1 GoF variants contribute to an interstitial lung disease phenotype, thereby expanding the spectrum of IFIH1-related disorders?

Study design and methods: Among 559 children with interstitial lung disease (chILD) and exome sequencing as part of their diagnostic work-up, 12 rare heterozygous IFIH1 variants were identified. Of these, 10 were missense variants of unknown significance, which were functionally assessed in vitro using luciferase assay and ISG-expression profiling. Genome-wide RNA analysis was performed on available patient samples to explore broader transcriptional effects.

Results: Four variants with increased basal IFNβ transcription in vitro and elevated ISG expression in vivo indicating GoF behaviour were identified. Disease severity correlated with GoF potential of the respective variant. Two patients harbouring IFIH1 variants with strong GoF activity displayed multisystem involvement and died from respiratory failure at 3 and 4 months of age, respectively. Two additional patients showed milder phenotypes with chronic lung disease stabilizing by the age of 8 and 10 years, respectively. Lung biopsies showed alveolar hypoplasia and alveolar macrophage pneumonia (=desquamative interstitial pneumonia) of varying severity.

Interpretation: We report a dominant interstitial lung disease phenotype in individuals harbouring novel IFIH1 variants, expanding IFIH1-related disease to the group of type I interferonopathies with pulmonary manifestations like STING-associated vasculopathy with onset in infancy (SAVI) and COPA syndrome.

Background: Ventilator-associated pneumonia (VAP) is a major healthcare-associated infection in critically ill children, primarily driven by microaspiration around the endotracheal tube cuff.

Research question: Does continuous automatic cuff pressure monitoring (CACPM) reduce the incidence of VAP compared to intermittent manual cuff pressure monitoring (IMCPM) in critically ill pediatric patients requiring mechanical ventilation?

Study design and methods: In this open-label, randomized controlled superiority trial, pediatric patients requiring mechanical ventilation for ≥48 hours were randomly assigned (1:1) to either CACPM or IMCPM. The target cuff pressure was strictly maintained at 20-25 cmH₂O. The primary outcome was the proportion of patients developing VAP within 28 days following intubation, evaluated in the intention to treat population. Secondary outcomes included time to VAP diagnosis and target pressure compliance. Statistical approaches included Kaplan-Meier survival analysis and multivariable Cox proportional hazard regression.

Results: Among 241 randomized patients, ITT analysis showed lower VAP with CACPM than IMCPM (13.3% vs 24.0%; risk difference, -10.6 percentage points; 95% CI, -20.3 to -0.8; P=0.034), with similar PP findings (15.0% vs 26.6%; P=0.044). ITT incidence density was 15.7 vs 27.1 per 1,000 ventilator-days (IRR, 1.73; 95% CI, 0.94-3.18; P=0.080). Unadjusted time-to-VAP was nonsignificant (HR, 1.80; 95% CI, 0.976-3.321; P=0.060), whereas adjusted Cox analysis narrowly indicated a higher VAP hazard with IMCPM (HR, 1.90; 95% CI, 1.024-3.510; P=0.042). Target-pressure compliance was higher with CACPM (P<0.001).

Interpretation: CACPM significantly reduces the proportion of critically ill pediatric patients developing VAP compared with IMCPM. This preventive effect appears directly linked to improved target pressure compliance, suggesting that automated regulation could be a valuable addition to pediatric VAP prevention strategies.

Clinical trial registration: ClinicalTrials.gov, NCT05918172.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is an ANCA-associated vasculitis characterized by eosinophilic asthma and ENT involvement. Both mepolizumab and benralizumab have demonstrated efficacy in EGPA and are now considered front-line options. In patients who do not respond to mepolizumab, benralizumab may be a valuable alternative owing to its enhanced depletion of eosinophils. We assessed the efficacy for and safety of switching from mepolizumab to benralizumab in EGPA.

Research question: Is benralizumab effective and safe in EGPA patients after mepolizumab failure, given its enhanced depletion of eosinophil?

Study design and methods: We conducted a retrospective European multicenter study including 68 adult EGPA patients who received benralizumab after mepolizumab failure. Complete (CR) and partial (PR) response were defined as BVAS=0, with prednisone ≤4 mg/day and > 4 mg/day, respectively.

Results: Median benralizumab follow-up period was 28 [20-39] months. CR and PR were achieved in 32% and 25% of patients, and maintained at last follow-up in 19% and 16%. Median time to CR was 6 [4-12] months. Forced expiratory volume in one second improved from 73% to 79%, and 38% of patients discontinued glucocorticoids. Vasculitis flares occurred in six patients. Primary mepolizumab failure was associated with lower CR rates (OR 0.19, 95% CI 0.06-0.60). Benralizumab was discontinued in 18% due to persistent respiratory symptoms. Adverse events occurred in five patients, including two severe SARS-CoV-2 infections.

Interpretation: In EGPA patients with persistent respiratory manifestations after mepolizumab failure, switching to benralizumab could represent a valuable option, improving lung function and reducing glucocorticoid use. Further prospective studies are needed to optimize sequencing and patient selection.

Background: Asthma biologics are highly effective in reducing exacerbations. Improvement in exacerbations after biologic initiation is often attributed to treatment effect.

Research question: What proportion of biologic-eligible severe asthma patients improve without biologic therapy, and what characterises those who remain frequent exacerbators?

Study design and methods: Biologic-naïve adults with severe asthma were identified in nationwide UK electronic medical records. Year 0 was defined as the first year patients met severe asthma criteria with ≥3 systemic corticosteroid-treated exacerbations (biologic-eligible). Post-eligibility exacerbation trajectories were identified using longitudinal k-means. Sensitivity analyses included alternative k and a lower exacerbation threshold (≥2/year). Covariates included the highest blood eosinophil count, inhaled corticosteroid (ICS) dose and comorbidities.

Results: Among 10,078 biologic-eligible adults (median age 51 years; 71% female), we identified three exacerbation trajectories: (1) Remitting-stable (70%, n=7,091), with sustained improvement to <3 exacerbations/year even though ICS reduced after peak exacerbation year; (2) Chronic-frequent (20%, n=1,969), with persistently frequent exacerbations (median 5/year); (3) Refractory-frequent (10%, n=1,018), with high ongoing oral corticosteroid exposure (median >10 courses/year). Results were consistent across sensitivity analyses. Remitting-stable patients were least likely to have bronchiectasis but were otherwise similar in demographics and allergic comorbidities. Blood eosinophil count was higher in the chronic-frequent group (Year 0 median 0.30×10⁹/L) compared with remitting-stable (0.23×10⁹/L) and refractory-frequent groups (0.21×10⁹/L, p<0.001); this was evident several years before meeting biologic exacerbation criteria.

Interpretation: Over two-thirds of biologic-eligible patients improved with standard care alone. Chronic-frequent exacerbators had higher blood eosinophil counts, even years before meeting biologic criteria, suggesting a distinct disease phenotype.

Background: Sotatercept, a ligand trap for TGF-β family members, has been shown to improve exercise capacity and decrease pulmonary vascular resistance (PVR) in adults with pulmonary arterial hypertension. Limited data exist describing the use of sotatercept in children with pulmonary hypertension (PH).

Research question: What is the safety and efficacy of sotatercept as add-on therapy in children with PH.

Study design and methods: This is a multi-center, retrospective study of children and young adults ≤ 21 years of age with pediatric PH treated by programs in the Pediatric PH Network and institutional registries. Demographic data and clinical characteristics before and after sotatercept initiation were collected.

Results: Sixty-six subjects received sotatercept as add-on therapy for a median duration of 323 days (Interquartile range 239, 500). Forty (60%) were female with median age 15.3 years (range 3.0 - 21.0) at initiation of sotatercept, and 61 with Group 1 (92%) PH. WHO functional class improved in 51% and did not worsen in any subjects (p < 0.0001). Subjects experienced significant improvement in six-minute walk distance (median 31 m, p=0.0003, n=40), NT-proBNP (median decrease 378 pg/ml, p< 0.0001, n=26), mean pulmonary artery pressure (median decrease 17 mmHg, p<0.0001, n=21), and PVR (median decrease 4.4 WUi, p=0.0011, n=21). Parenteral prostacyclin was weaned or discontinued in 13 of 38 patients. Adverse events occurred in 33 (50%) subjects with bleeding in 15 (23%). No patients had escalation of PH therapy, were hospitalized for clinical worsening, underwent lung transplant, or died.

Interpretation: Pediatric PH patients treated with sotatercept as add-on therapy demonstrated improvement in functional class and other PH disease indicators and was generally well tolerated.