Daily Respiratory Research Analysis

IMPORTANCE: Sepsis is heterogeneous, and the optimal strategy for tailoring immunotherapy is uncertain. OBJECTIVE: To investigate whether precision immunotherapy guided by the presence of macrophage activation-like syndrome or sepsis-induced immunoparalysis improves organ dysfunction by day 9. DESIGN, SETTING, AND PARTICIPANTS: A randomized, double-blind, double-dummy, placebo-controlled clinical trial conducted in 6 countries. Patients with sepsis, defined by Sepsis-3, were included if they had community-acquired or hospital-acquired pneumonia or ventilator-associated pneumonia or bacteremia and sepsis and had displayed either macrophage activation-like syndrome (blood ferritin >4420 ng/mL) or sepsis-induced immunoparalysis (blood ferritin ≤4420 ng/mL and <5000 human leukocyte antigen DR receptors on CD45/CD14 monocytes). The first patient was enrolled August 5, 2021, and the last follow-up, April 29, 2024. INTERVENTIONS: Eligible patients were randomized to receive standard care and precision immunotherapy or standard care and placebo. Those in the precision immunotherapy group with macrophage activation-like syndrome received anakinra intravenously (IV) and placebo subcutaneously, and those with sepsis-induced immunoparalysis received subcutaneous recombinant human interferon gamma and IV placebo. Those in the placebo group received both IV and subcutaneous placebo. Treatment was administered for up to 15 days. MAIN OUTCOMES AND MEASURES: The primary end point was a decrease of at least 1.4 points in the mean Sequential Organ Failure Assessment (SOFA) score from baseline by day 9. The SOFA score evaluates 6 organ systems, ranging from 0, no dysfunction, to 4, failure, and the total score ranges from 0, normal, to 24, most severe form of multiorgan failure. Key secondary outcomes included 28-day mortality. RESULTS: Of 672 patients assessed for eligibility, 281 were randomized and 276 were included in the primary analysis population (mean [SD] age, 70 [13] years; 93 females [33.7%]; median baseline SOFA score, 9 [IQR, 7-11]). The SOFA decrease end point was attained by 46 of 131 patients (35.1%) in the precision immunotherapy group and by 26 of 145 patients (17.9%) in the placebo group (difference, 17.2% [95% CI, 6.8% to 27.2%]; P = .002). Mortality at 28 days was not statistically significantly different between groups. A total of 1069 serious treatment-emergent adverse events (88.8%) were reported; increased incidence of anemia was noted in the anakinra group; and hemorrhage in the recombinant human interferon gamma group. CONCLUSIONS AND RELEVANCE: Among patients with sepsis, precision immunotherapy targeting macrophage activation-like syndrome and sepsis-induced immunoparalysis improved organ dysfunction by day 9 compared with placebo. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04990232.

BACKGROUND: Whether the addition of bevacizumab to a programmed cell death protein-1 (PD-1) inhibitor plus chemotherapy can provide further survival benefits as first-line treatment in non-squamous non-small-cell lung cancer (NSCLC) without EGFR sensitising mutations, or ALK/ROS1 rearrangements, is unknown. We evaluated serplulimab (an anti-PD-1 antibody) plus HLX04 (a bevacizumab biosimilar) and chemotherapy in non-squamous NSCLC. METHODS: ASTRUM-002 is a randomised, double-blind, multicentre, phase 3 trial with a three-arm design. Patients (aged ≥18 years and ≤75 years) with locally advanced or metastatic non-squamous NSCLC without EGFR sensitising mutations or ALK/ROS1 rearrangements and previous systemic therapy were randomly assigned (1:1:1; stratified by PD-L1 expression, smoking history, and brain metastasis) to receive serplulimab (4·5 mg/kg intravenously) plus HLX04 (15 mg/kg intravenously) and chemotherapy (pemetrexed and carboplatin; group A), serplulimab plus chemotherapy plus HLX04 placebo (group B), or chemotherapy plus serplulimab placebo plus HLX04 placebo (group C). The primary endpoint was the blinded independent central review assessed progression-free survival per the Response Evaluation Criteria in Solid Tumors version 1.1, assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT03952403, and is complete. FINDINGS: Between Nov 25, 2019, and June 15, 2022, 642 patients were enrolled across 72 hospitals in China; six in the safety run-in phase and the remaining 636 patients were randomised to group A (212 patients), B (214), or C (210). 465 (73%) were male, 171 (27%) were female, and 599 (94%) were of Han ethnicity. By the data cutoff date of June 15, 2023, the median follow-up duration was 23·4 months (95% CI 21·6-24·9) in group A, 23·1 (21·4-25·6) in group B, and 23·0 (20·7-25·6) in group C. Median progression-free survival was 12·6 months (95% CI 8·7-14·0; 123 events) in group A, 11·0 months (95% CI 8·4-12·7; 130 events) in group B, and 5·6 months (95% CI 4·8-6·8; 156 events) in group C. A significant reduction was seen in risk of progressive disease or death for patients in group B compared with group C (hazard ratio [HR] 0·55, 95% CI 0·43-0·69; p<0·0001). No significant improvement in progression-free survival was seen for group A compared with group B (HR 0·86, 0·67-1·11; p=0·25). Treatment-related serious adverse events occurred in 82 (39%) patients in group A, 79 (37%) in group B, and 51 (24%) in group C. Grade 3 or worse treatment-related adverse events occurred in 149 (71%) patients in group A, 142 (66%) in group B, and 119 (57%) in group C. Treatment-related adverse events leading to death occurred in ten (5%) patients in group A, five (2%) in group B, and seven (3%) in group C. INTERPRETATION: The addition of serplulimab to chemotherapy led to significantly longer progression-free survival in patients with locally advanced or metastatic non-squamous NSCLC compared with chemotherapy alone and represents an alternative first-line treatment option for this patient population. HLX04 plus serplulimab and chemotherapy did not confer further statistical benefit compared with serplulimab plus chemotherapy. FUNDING: Shanghai Henlius Biotech.

IMPORTANCE: Respiratory syncytial virus (RSV) infection has recently been recognized as common among adults, but data on the burden of cardiovascular disease (CVD) beyond the immediate acute phase are lacking. OBJECTIVE: To estimate the 365-day absolute excess risk (risk difference) of composites of CVD and their individual components following laboratory-confirmed RSV infection in adults. DESIGN, SETTING, AND PARTICIPANTS: This nationwide, registry-based, matched cohort study was conducted using Danish national health registries. Adults aged 45 years or older on January 1, 2019, with a laboratory-confirmed RSV infection between January 1, 2019, and December 31, 2024, were matched 1:1 on age, sex, and preexisting comorbid conditions to individuals without RSV infection. Similar matched cohorts were established for influenza infection, hip fracture, and urinary tract infection without sepsis as control groups. EXPOSURE: Laboratory-confirmed RSV infection. MAIN OUTCOMES AND MEASURES: The primary outcomes were major adverse cardiovascular events, comprising ischemic heart disease, stroke, and heart failure, and any cardiovascular event, comprising major adverse cardiovascular events together with arrhythmias, venous thromboembolism, and inflammatory heart disease. Matched individuals were followed up for up to 365 days after the index date. Absolute risk differences and 95% CIs were calculated at 30 and 365 days using cumulative incidences derived from the Aalen-Johansen estimator. RESULTS: The study included 17 494 matched individuals (mean [SD] age, 71.8 [12.0] years; 57.6% female). At 365 days, 665 any cardiovascular events had occurred among 8747 individuals with RSV infection and 257 among 8747 individuals without infection, corresponding to a risk difference of 4.69 percentage points (95% CI, 4.02-5.36 percentage points). The largest 365-day risk differences for any cardiovascular event were observed in hospitalized patients (6.61 percentage points [95% CI, 5.70-7.52 percentage points]), older individuals (eg, 7.93 percentage points [95% CI, 5.34-10.53 percentage points] for those aged 85-94 years), and preexisting CVD (11.95 percentage points [95% CI, 8.80-15.10 percentage points ]) or diabetes (7.50 percentage points [95% CI, 4.53-10.47 percentage points]). The 1-year cardiovascular event risk following RSV was comparable to that following influenza infection. CONCLUSIONS AND RELEVANCE: This cohort study of adults aged 45 years or older with RSV infection found a significant excess risk of cardiovascular events over 1 year, comparable in magnitude to influenza infection. These findings underscore the importance of RSV as a potential risk factor for cardiovascular morbidity and highlight the need for vaccination to mitigate this burden.