Daily Respiratory Research Analysis

Electrical impedance tomography (EIT)-guided positive end-expiratory pressure (PEEP) titration may optimize ventilation and reduce ventilator-induced lung injury in acute respiratory distress syndrome (ARDS). We compared EIT-guided PEEP with low PEEP/FiO₂ strategy in patients with moderate-to-severe ARDS. In this randomized controlled trial, 108 patients with PaO₂/FiO₂ below 200 mmHg were allocated to EIT-guided PEEP after a recruitment maneuver (n = 56) or low PEEP/FiO₂ strategy (n = 52). Patients in the EIT group underwent PEEP titration guided by the intersection point between alveolar overdistension and collapse during a decremental PEEP trial. Primary outcomes were oxygenation (PaO₂/FiO₂) and static compliance. Secondary outcomes included mortality, ventilator-free days, ICU stay, barotrauma, rescue therapies, and sequential organ failure assessment (SOFA) score changes. On day 1, oxygenation was higher with EIT (mean PaO₂/FiO₂ 180 vs. 159 mmHg; p = 0.036). Static compliance was greater at both day 1 (26 vs. 23 mL/cmH₂O; p = 0.016) and day 2 (27 vs. 24 mL/cmH₂O; p = 0.029). Driving pressure was lower with EIT at day 1 (16 vs. 17 cmH₂O; p < 0.001) and day 2 (15 vs. 17 cmH₂O; p = 0.005). SOFA scores improved more in the EIT group (day 1: - 1 vs. 0, p = 0.013; day 2: - 1 vs. - 0.5, p = 0.015). Twenty-eight-day mortality was lower with EIT (29 vs. 44%), although not statistically significant (p = 0.090). ICU stay, ventilation duration, barotrauma, ECMO use, and rescue therapies were similar. Benefits were most pronounced in patients with severe ARDS. EIT-guided PEEP improved oxygenation, lung mechanics, and reduced organ dysfunction in moderate-to-severe ARDS, particularly in severe cases. It showed a trend toward reduced mortality and may serve as a practical bedside tool for lung-protective ventilation. Larger multicenter trials are needed to confirm its clinical benefits.Trial registration: ClinicalTrials, NCT06733168. Registered on 13/12/2024, https://clinicaltrials.gov/study/NCT06733168.

BACKGROUND: The SOURCE phase 3 oral corticosteroid (OCS)-sparing study of tezepelumab indicated an OCS-sparing effect with tezepelumab versus placebo in patients with OCS-dependent asthma and baseline blood eosinophil counts (BECs) of at least 150 cells per μL. The WAYFINDER study aimed to further evaluate the ability of tezepelumab to reduce or discontinue OCS use in a larger cohort of patients with OCS-dependent severe, uncontrolled asthma. METHODS: WAYFINDER was a phase 3b, multicentre, single-arm, open-label, OCS-sparing study. Adults (aged 18-80 years) with severe, uncontrolled asthma receiving a maintenance OCS dose of 5-40 mg per day (or equivalent) of prednisone or prednisolone were recruited from 68 clinical centres across 11 countries (Argentina, Belgium, Bulgaria, France, Germany, Latvia, Mexico, Poland, Spain, UK, and USA). Participants received tezepelumab 210 mg subcutaneously once every 4 weeks for up to 52 weeks. The co-primary endpoints, assessed at weeks 28 and 52, were the proportion of participants who reduced their prescribed maintenance OCS dose to 5 mg per day or less without loss of asthma control and the proportion of participants who discontinued OCS without loss of asthma control. OCS dose reductions to below 5 mg per day were contingent on participants demonstrating preserved adrenal function. This completed study was registered with ClinicalTrials.gov (NCT05274815). FINDINGS: WAYFINDER was conducted between May 17, 2022, and Sept 9, 2024. Overall, 382 participants were enrolled and 298 participants (206 female [69·1%]) received tezepelumab and were included in the efficacy and safety analyses. The mean baseline maintenance OCS dose was 10·8 (SD 6·5) mg per day. The proportion of participants who had a maintenance OCS dose of 5 mg per day or less without loss of asthma control was 265 of 298 (88·9% [95% CI 84·8-92·3]) at week 28 and 268 of 298 (89·9% [85·9-93·1]) at week 52. The proportion of participants who discontinued OCS without loss of asthma control was 96 of 298 (32·2% [26·9-37·8]) at week 28 and 150 of 298 (50·3% [44·5-56·2]) at week 52. OCS reduction and discontinuation were achieved across pre-specified subgroups based on baseline BEC, fractional exhaled nitric oxide level, or allergy status. Serious adverse events were reported in 28 (9·4%) of 298 participants (asthma [13 participants] and pneumonia [three participants] were the most common), and four participants (1·3%) had adverse events leading to tezepelumab discontinuation. Two participants died during the study but neither death was considered to be causally related to tezepelumab treatment. INTERPRETATION: After 52 weeks of open-label tezepelumab treatment, nearly 90% of patients with OCS-dependent severe, uncontrolled asthma had a maintenance OCS dose of 5 mg per day or less and more than 50% completely discontinued OCS, while maintaining asthma control. These findings indicate that tezepelumab treatment can help enable patients with severe asthma to reduce their OCS use and its associated burden, with broad applicability across patient phenotypes. FUNDING: AstraZeneca and Amgen.

The global spread of highly pathogenic avian influenza A(H5N1) viruses poses a serious pandemic threat. While sustained human-to-human transmission has not occurred, widespread circulation in birds, increased detection in mammals, and occasional human spillovers underscore the need for safe and effective vaccines. We evaluated an H5 mRNA vaccine candidate in ferrets using recent clade 2.3.4.4b A(H5N1) human isolates. Vaccination elicited strong neutralizing antibodies, conferred robust protection against lethal challenge, and significantly reduced viral titers. In a direct contact transmission model, mRNA vaccination decreased virus shedding in inoculated ferrets and reduced onward transmission; it also protected vaccinated contact ferrets from infection following exposure to virus-shedding, unvaccinated ferrets. Additionally, sera from vaccinated animals cross-neutralized clade 2.3.2.1e human viruses to varying degrees, depending on the strain. These findings demonstrate that H5 mRNA vaccination not only protects against disease but also reduces transmission, supporting its potential as a key tool for pandemic preparedness.