Daily Respiratory Research Analysis

BACKGROUND: Pneumocystis jirovecii pneumonia in HIV-negative immunocompromised patients has a hospital mortality rate of 30-50%. Adjunctive corticosteroids improve outcomes of P jirovecii pneumonia in HIV-positive patients. The aim of this trial was to assess the effects of early adjunctive corticosteroid therapy for 21 days in HIV-negative patients with P jirovecii pneumonia responsible for acute hypoxaemia respiratory failure. METHODS: This multicentre, double-blind, randomised controlled trial was conducted at 27 hospitals in France. We included patients with acute respiratory failure, aged 18 years or older with mild-to-severe hypoxaemia, microbiological documentation of P jirovecii pneumonia, and anti-Pneumocystis treatment duration of less than 7 days. Patients were randomly assigned (1:1) to the corticosteroid group (adjunctive corticosteroid therapy of methylprednisolone intravenously, 30 mg twice per day from days 1 to 5, 30 mg once per day from days 6 to 10, and 20 mg once per day until day 21) or placebo group (2 mL or 3 mL syringes of isotonic saline intravenously) using a web-based system. Permutation blocks of fixed size unknown to the local investigators were used. Stratification factors were centre, long-term corticosteroid treatment started more than 1 month before enrolling in the trial, underlying disease (malignancy vs other), and oxygen needs at randomisation (<6 vs ≥6 L per min). The primary outcome was all-cause 28-day mortality defined as the proportion of patients who died within 28 days, analysed in the intention-to-treat (ITT) population. This trial was registered on ClinicalTrials.gov, NCT02944045 (closed). FINDINGS: From Feb 23, 2017, to Feb 23, 2024, 466 patients with acute respiratory failure were assessed for eligibility. Of those, 240 were excluded and 226 patients were randomly assigned (114 assigned to the placebo group and 112 assigned to the corticosteroid group). The ITT population included 111 patients in the placebo group and 107 in the corticosteroid group. Median age was 67 years (IQR 59-73). 126 (58%) patients were male and 92 (42%) were female. Nearly all patients (208 [95%]) were in the ICU or intermediate care at randomisation. The median time from P jirovecii pneumonia diagnosis to corticosteroid therapy initiation was 3 days (IQR 2-5). Patients received trial treatment for 13 days (range 7-20). All-cause 28-day mortality occurred in 36 (32·4%) patients in the placebo group versus 23 (21·5%) in the corticosteroid group (mean difference 10·9% [95% CI -0·9 to 22·5]; p=0·069). There were no significant differences in safety outcomes between groups, especially for all secondary infections (38 [34·2%; 95% CI 25·4 to 43·1] patients in the placebo group vs 25 [23·4%; 15·3 to 31·4] in the corticosteroid group) or insulin needs (25 [22·5%; 15·1 to 31·4] vs 33 [30·8%; 22·3 to 40·5]). INTERPRETATION: In immunocompromised HIV-negative patients with P jirovecii pneumonia, adjunctive corticosteroid treatment did not significantly decrease 28-day mortality. FUNDING: French Ministry of Health.

IMPORTANCE: While biologic therapies targeting type 2 (T2) inflammation reduce acute exacerbation rates in children with asthma and T2 inflammation, exacerbations still occur, and the underlying molecular mechanisms are poorly defined. OBJECTIVE: To identify multiple distinct molecular mechanisms implicated in asthma exacerbations by characterizing respiratory illnesses among urban children with eosinophilic asthma enrolled in a clinical trial comparing treatment with mepolizumab vs placebo. DESIGN, SETTING, AND PARTICIPANTS: This is a secondary analysis of the Mechanisms Underlying Asthma Exacerbations Prevented and Persistent With Immune-Based Therapy: A Systems Approach Phase 2 (MUPPITS-2) double-blind, placebo-controlled, parallel-group, randomized clinical trial comparing treatment with mepolizumab vs placebo among children with exacerbation-prone asthma in low-income urban centers in 9 US cities. Data analysis was performed from September 2022 to April 2025. INTERVENTION: Participants were randomized to receive either mepolizumab (aged 6-11 years: 40 mg; aged 12-17 years: 100 mg) or matching placebo by subcutaneous injection once every 4 weeks for 52 weeks. MAIN OUTCOMES AND MEASURES: The primary measurement was a transcriptomic modular analysis by RNA sequencing of nasal samples obtained during acute respiratory illnesses. Associations among upper airway transcriptional signatures, the clinical outcome of respiratory illnesses, and pulmonary functions were investigated. RESULTS: Of the 290 participants enrolled in the MUPPITS-2 trial, 108 participants (median [IQR] age, 10.0 [9.0-13.0] years; 48 [44%] female) were sampled during 176 acute respiratory illness events. During illness events resulting in asthma exacerbations, children receiving mepolizumab demonstrated decreased expression of an eosinophil-associated module associated with T2 inflammation (log2 fold change [FC] estimate, -0.60; false discovery rate [FDR] < .05) but increased expression of gene modules associated with epithelial and macrophage inflammatory pathways relative to children receiving placebo (log2 FC estimates, 0.22-0.85; FDR < .05). Both groups showed higher expression of mucus secretion and cellular stress response pathways during exacerbations relative to nonexacerbation illnesses. The mepolizumab group demonstrated upregulation of epithelial inflammatory pathways in exacerbations irrespective of a respiratory virus, while macrophage pathways contributed specifically to viral exacerbations. Three distinct, semiorthogonal inflammatory axes were shown to underlie the majority of the heterogeneity among exacerbations in the 2 groups. CONCLUSIONS AND RELEVANCE: The study's findings implicate multiple alternative inflammatory pathways associated with the epithelium and macrophages, as well as mucus hypersecretion, as mechanisms of residual acute exacerbations in children receiving mepolizumab. Further, they indicate that multiple distinct inflammatory axes can independently contribute to asthma exacerbations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03292588.

BACKGROUND: Elderly patients are prone to secretion retention and exacerbated lung infections due to weakened respiratory muscle strength and reduced ability to cough and expectorate. Airway clearance techniques (ACTs) can help to clear airway secretions, but objective bedside assessment of secretion clearance efficacy is lacking. Electrical impedance tomography (EIT) can dynamically monitor lung ventilation and provide a basis for clinical decision-making. METHODS: This study was a prospective randomized controlled trial that included 50 elderly patients with severe pneumonia, who were randomized into EIT and non-EIT groups. The EIT group received personalized ACTs guided by real-time EIT imaging with dynamic adjustment of posture, percussion intensity, and active circulatory breathing technique (ACBT) frequency, whereas the non-EIT group received fixed-schedule ACTs (postural drainage every 2 h + percussion/vibration twice daily) without EIT feedback. The main observation indices included Clinical Pulmonary Infection Score (CPIS), respiratory mechanics indices, blood gas analysis indices, and extubation success rate. RESULTS: The EIT group showed significantly lower CPIS scores (p = 0.0137 on Day 7), higher dynamic compliance (p = 0.0193), lower airway resistance (p = 0.0039), lower peak airway pressure (p = 0.0288), and higher oxygenation index (p = 0.0143 on Day 5 and p = 0.0005 on Day 7) than the non-EIT group. The extubation success rate was significantly higher in the EIT group (88% vs. 56%, p = 0.0255). Additionally, the EIT group demonstrated progressive improvements in ventilation in specific regions (D7 vs. D1: p = 0.0004 for region of interest [ROI]3; p = 0.0059 for ROI4) and a significant decrease in the global inhomogeneity index at D7 (D7 vs. D1: p = 0.0025). CONCLUSION: EIT-guided ACT is safe and enhances treatment efficacy by significantly improving respiratory function and extubation success rate in elderly patients with severe pneumonia.