American journal of respiratory and critical care medicine最新文献

Rationale: Rademikibart (formerly CBP-201) is an IL-4Rα-targeting antibody.

Objectives: To evaluate rademikibart in adults with moderate-to-severe, persistent, uncontrolled asthma.

Methods: In this global phase 2b trial (NCT04773678), 322 patients were randomized 1:1:1 to two rademikibart groups (150 mg or 300 mg every other week, following a 600 mg loading dose) or placebo, administered subcutaneously, for 24 weeks.

Measurements and main results: Prebronchodilator (trough) forced expiratory volume in the first second of expiration (FEV₁) at Week 12 (primary endpoint) improved with rademikibart 150 mg and 300 mg: least squares mean changes (95% CI), above placebo, were +140 mL (+44-236 mL; p=0.005) and +189 mL (+92-286 mL; p<0.001), respectively. Prebronchodilator trough FEV₁ improvements occurred rapidly during Week 1, were sustained through Week 24, and greatest in patients with high baseline blood eosinophils (patients with ≥300 eosinophils/mL experienced placebo-adjusted FEV₁ improvement at Week 24 of +420 mL [95% CI, +239-600 mL] in the 300 mg group). Rapid and sustained statistically significant improvements were also observed in percent predicted FEV₁ and Asthma Control Questionnaire score across 24 weeks. Through Week 24, proportions of patients with ≥1 exacerbation were 7.5% (150 mg) and 9.3% (300 mg) vs 16.7% (placebo). 88% of patients completed treatment. Treatment-emergent adverse events (TEAEs) were generally similar to placebo, and no eosinophilia was observed. Injection site reactions were mostly mild. The most common TEAEs (10-12% of patients) were cough, COVID-19, and dyspnea.

Conclusions: Rapid and sustained improvements in lung function and asthma control were gained across 24 weeks of rademikibart therapy. Clinical trial registration available at www.

Clinicaltrials: gov, ID: NCT04773678.

Background: A subset of asthma patients have airway pathology characterized by a thickened subepithelial basement membrane zone ("BMZ-thick asthma").

Objectives: To characterize the clinical features of BMZ-thick asthma and to determine if BMZ thickness accompanies specific patterns of inflammation in the airway epithelium.

Methods: Design-based stereology was used to quantify BMZ thickness in endobronchial biopsy tissue sections from 109 asthma patients and 41 healthy controls from the Severe Asthma Research Program-3 whose participants had undergone spirometry and gene expression profiling in airway epithelial brushings.

Results: The upper 90th percentile value for BMZ thickness in the healthy cohort was 2.9 µM, and 35% of the asthma cohort had values above this upper limit. Compared to BMZ-thin asthma patients, BMZ-thick asthma patients were younger and had higher blood eosinophil numbers and serum immunoglobulin E levels that were specific to animal proteins. Mean pre-bronchodilator FEV1 was significantly lower in BMZ-thick than in BMZ-thin patients, but post-bronchodilator FEV1 was not. Upregulation of genes signifying interleukin-13 activation and presence of mast cells were evident in epithelial brushings in BMZ-thick patients, but gene signatures for activation by interferon gamma or interleukin-17 were not.

Conclusions: A thickened BMZ marks a subset of younger asthma patients characterized by higher IgE levels to animal aeroallergens and by increased bronchomotor tone occurring in the context of airway epithelial cells activated by interleukin-13 and infiltrated by mast cells.

Rationale: Patients with acute respiratory distress syndrome (ARDS) have a reduction in functional lung volume resulting in increased respiratory system elastance (Ers); however, the extent of this increase varies by patient. Patients with high Ers are at risk of excess lung-distending pressures and may derive greater clinical benefit from neuromuscular blockade (NMB).

Objectives: To evaluate whether the effect of early NMB administration on mortality varies according to baseline physiological and biological biomarkers of lung injury, including Ers.

Methods: We conducted a secondary analysis of the ROSE trial. Bayesian logistic regression modelling was employed to estimate the posterior probability of NMB effect moderation by baseline Ers, ventilatory ratio, and select ARDS plasma biomarkers on 90-day mortality.

Measurements and main results: The probability of mortality benefit with NMB increased substantially with higher baseline Ers (posterior probability of interaction, 92%; interaction odds ratio 0.76, 90% credible interval (CrI) 0.59-0.99). In patients with Ers ≥2cm H₂O/(mL/kg), the posterior probability of benefit was 96% (median absolute risk reduction 9%, 90% CrI 0.5-17.9%). The effect of NMB did not vary meaningfully according to ventilatory ratio (posterior probability of interaction, 62%) or baseline plasma levels of receptor for advanced glycation end-products, tumor necrosis factor receptor-1, interleukin-6 or -8 (posterior probabilities of interaction: 12%, 18%, 44% and 22% respectively).

Conclusions: These findings suggest that the mortality benefit of NMB varies with baseline Ers. High Ers may represent a physiological phenotype of ARDS. Future prospective testing to confirm benefit in this potentially treatment-responsive group is needed.

Rationale: Extended continuous positive airway pressure (eCPAP) in the neonatal intensive care unit (NICU) for stable preterm infants increases lung volumes. Its effect on lung growth after discharge is unknown.

Objective: To assess whether 2-weeks of eCPAP in stable preterm infants is associated with increased alveolar volume (V_A) at 6-months corrected age.

Methods: Randomized controlled trial conducted at Oregon Health & Science University. Outpatient assessors unaware of treatment assignment. 100 infants randomized to eCPAP versus CPAP discontinuation (dCPAP) to room air.

Measurements: The primary outcome was V_A by the single breath hold technique at 6-months corrected age. Secondary outcomes included lung diffusion capacity to carbon monoxide (D_L) and forced expiratory flows (FEFs). Functional residual capacity (FRC) was measured in the NICU.

Main results: Infants randomized to eCPAP (n=54) versus dCPAP (n=46) had the following measurements shown as adjusted mean [SE] : V_A (500.2 [24.9 ] vs 418.1 [23.4] mL; adjusted mean difference, 82.1 [ 95% CI, 8.3-155.9]; p =0.033); D_L (3.4 [0.2] vs 2.8 [0.1] mL/min/mmHg; adjusted mean difference, 0.6 [95% CI, 0.1-1.1]; p = 0.018); FEF₅₀ (500.6 [18.2] vs 437.9 [17.9] mL/sec; adjusted mean difference, 62.7 [95% CI 4.5-121.0]; p = 0.039); FEF_25-75 (452.0 [17.4] vs 394.4 [17.4] mL/sec; adjusted mean difference, 57.5 [95% CI 1.3-113.8]; p=0.046).

Conclusions: Infants randomized to eCPAP vs dCPAP had significantly increased V_A at 6-months corrected age. D_L and FEFs were also increased. Extending CPAP in stable preterm infants in the NICU may be a non-pharmacologic and safe therapy to promote lung growth. Clinical trial registration available at www.

Clinicaltrials: gov, ID: NCT04295564.

Applying mechanical ventilation and selecting ventilatory strategies in patients with acute brain injuries, especially those with lung damage, is challenging. Static (positive-end-expiratory-pressure) and dynamic (intra-tidal) changes in ventilator pressure, via complex pathways, influence cerebral arterial inflow and cerebral venous pressure and thus, cerebral blood volume and intracranial pressure. In this process, the relationship between airway pressure and pleural and trans-alveolar pressures, heavily affected by elastance of chest wall and lung, respectively, plays a central role. This relationship determines the extent to which a static and dynamic increase in airway pressure affect the cardiac function and venous return curves, which govern the static and dynamic arterial and central venous pressures. The integrity of cerebral autoregulation determines whether static changes in arterial pressure alter cerebral arterial inflow. Conversely, dynamic changes in arterial pressure during the breath are followed by corresponding changes in cerebral arterial inflow, due to inability of autoregulation to control rapid arterial pressure fluctuations. The flow dynamics in the jugular veins and the relationship between intracranial and sagittal sinus pressures determine whether static and dynamic changes in central venous pressure alter cerebral venous pressure. Setting the ventilator and planning strategies should be individualized and guided by the complex, interactive effects among central nervous, respiratory and cardiovascular systems on cerebral blood volume and cerebral perfusion and intracranial pressures. Following a logical framework, the clinician may anticipate the likely effects of ventilator settings and strategies on cerebral hemodynamics, enabling a more individualized approach in setting the ventilator and planning ventilatory strategies.