Daily Respiratory Research Analysis

BACKGROUND: Anti-SARS-CoV-2 monoclonal antibodies (mAb) reduce the risk of hospitalization in outpatients with mild-to-moderate COVID-19. However, the efficacy of treatment with mAbs and other passive immunotherapies in patients hospitalized with severe COVID-19 is not clear. The objective of this study was to assess the clinical effect of passive immunotherapy and its heterogeneity according to baseline endogenous neutralizing antibody status and SARS-CoV-2 antigen level, in adults hospitalized with SARS-CoV-2 infection and severe COVID-19. METHODS AND FINDINGS: We carried out a two-stage individual participant data meta-analysis of six double-blind, randomized, placebo-controlled trials conducted under the Therapeutics for Inpatients with COVID-19 (TICO) and the similarly designed Inpatient Treatment with Anti-Coronavirus Immunoglobulin (ITAC) master protocols. Within each trial, three major outcomes (sustained recovery, mortality, and a composite safety outcome) were compared between treatment and placebo using Fine-Gray and Cox proportional hazards models. Trial-specific treatment differences for each of the three outcomes were pooled using a common effect meta-analysis. A total of 3,079 patients hospitalized for COVID-19 were enrolled in the six trials. Only 18% had received at least one dose of an anti-SARS-CoV-2 vaccine. Overall, the median plasma SARS-CoV-2 antigen level was 1,421 (IQR: 231-4,568) pg/mL, and 51% of patients were endogenous neutralizing antibody positive at study entry. The overall summary estimate of sustained recovery rate ratio (RRR) of the treatment versus placebo group was 1.06 (95% CI [0.99,1.14]), but this varied significantly by antibody serostatus. The RRR was 1.16 (95% CI [1.04,1.29]) among seronegative patients and 0.97 (95% CI [0.88,1.07]) in seropositive patients [p = 0.02 for interaction (the difference in RRR between seropositive and seronegative patients)]. The summary hazard ratio (HR) for mortality comparing treatment to placebo was 0.81 (95% CI [0.64,1.03]) overall, 0.69 (95% CI [0.50,0.95]) in seronegative patients, and 0.96 (95% CI [0.66,1.39]) in seropositive patients (interaction p = 0.18). There was no evidence that the treatment effect on any outcome differed according to antigen level, whether overall or within serostatus subgroups. In regards to the composite safety outcome, the overall summary HR comparing treatment group to placebo was 0.89 (95% CI [0.66,1.21]; Q = 3.47 [p = 0.63], I2 = 0.0%), and it was 0.83 (95% CI [0.70,0.99]) and 1.04 (95% CI [0.86,1.26]) in seronegative and seropositive patients, respectively. The main limitation of the methodology is that these results are limited to the analysis of the six trials in ACTIV-3/TICO and ITAC and are not intended to be a complete summary of all trials of passive immunotherapy. CONCLUSIONS: Passive immunotherapy might be a useful treatment option for hospitalized patients with COVID-19 if administered before the appearance of endogenous antibodies. Development of similar passive immunotherapy could also be especially important during the early stages of a viral pandemic, or as novel viral variants emerge.

Influenza A virus (IAV) is a respiratory pathogen of global concern. Entry of most IAVs is mediated by binding of viral hemagglutinin to cellular sialic acid, facilitating virus attachment. A subsequent interaction with a surface receptor(s) triggers viral uptake. Although multiple host factors involved in viral entry are known, the identity of these receptors remains unclear. Here, we utilized proximity labelling to acquire the interactome of epsin 1, an adaptor protein utilized by IAV for clathrin-mediated endocytosis, during virus internalization to identify them. We uncover neogenin (Neo1), a member of the immunoglobulin superfamily expressed in primary human airway cultures, as a potential epsin 1 interactor and virus receptor candidate. Knockdown of Neo1 led to a reduction in replication of H1N1, H2N2 and H5N1 IAVs in primary and immortalized lung cells. Moreover, human recombinant Neo1 was found to bind IAV with a KD of 21 ± 14 nM by atomic force microscopy and Neo1 could co-localize with incoming IAV at early times post-infection, as well as affect viral entry. As Neo1 can interact with IAV and its depletion impairs IAV entry, this study reveals its potential as an IAV internalization receptor.

IMPORTANCE: Transitioning from metered-dose inhalers to propellant-free dry-powder inhalers could reduce health care-related greenhouse gas emissions, but the clinical difference in outcomes that may be associated with this switch is uncertain. OBJECTIVE: To evaluate the clinical difference in outcomes associated with a July 2021 Veterans Health Administration (VHA) formulary change that replaced budesonide-formoterol metered-dose inhaler with fluticasone-salmeterol dry-powder inhaler for the treatment of chronic obstructive pulmonary disease and asthma. DESIGN, SETTING, AND PARTICIPANTS: This within-person, self-controlled case series (SCCS) and matched observational cohort study (cohort study) used data from the US Veterans Affairs health care system from January 2018 through December 2022. Veterans who were prescribed a combination inhaler before and after the formulary change were included in both the SCCS and cohort study. Data were analyzed between April 19, 2024, and April 4, 2025. EXPOSURES: Treatment with budesonide-formoterol metered-dose inhaler vs fluticasone-salmeterol dry-powder inhaler. MAIN OUTCOMES AND MEASURES: Rescue medication use (albuterol and prednisone fills), emergency department visits, and hospitalizations (all-cause, respiratory-related, and pneumonia-specific) were assessed. RESULTS: Following the VHA formulary change, 260 268 patients switched from budesonide-formoterol metered-dose therapy to fluticasone-salmeterol dry-powder therapy. In the SCCS (median [IQR] age, 71 [62-75] years; 91% male), among patients who switched inhalers and experienced the adverse outcomes of interest, treatment with fluticasone-salmeterol dry-powder inhaler therapy was associated with a 10% decrease in albuterol fills (incidence rate ratio [IRR], 0.90 [95% CI, 0.90-0.91]), a 2% increase in prednisone fills (IRR, 1.02 [95% CI, 1.01-1.03]), a 5% increase in all-cause emergency department visits (IRR, 1.05 [95% CI, 1.04-1.06]), an 8% increase in all-cause hospitalizations (IRR, 1.08 [95% CI, 1.06-1.09]), a 10% increase in respiratory-related hospitalizations (IRR, 1.10 [95% CI, 1.07-1.14]), and a 24% increase in pneumonia-specific hospitalizations (IRR, 1.24 [95% CI, 1.17-1.31]). In the cohort study of 258 557 patients (mean [SD] age, 68.9 [11.3] years; 94% male), those who switched to a fluticasone-salmeterol dry-powder inhaler had no difference in mortality (1.89% vs 1.90%; adjusted absolute difference, -0.01 percentage points [95% CI, -0.12 to 0.10 percentage points]) but had increases in all-cause hospitalizations (16.14% vs 15.64%; adjusted absolute difference, 0.49 percentage points [95% CI, 0.21-0.78 percentage points]), respiratory-related hospitalizations (3.15% vs 2.74%; adjusted absolute difference, 0.41 percentage points [95% CI, 0.27-0.55 percentage points]), and pneumonia-related hospitalizations (1.15% vs 1.03%; adjusted absolute difference, 0.12 percentage points [95% CI, 0.04-0.21 percentage points]) at 180 days after the switch compared with matched patients who did not switch. CONCLUSIONS AND RELEVANCE: The study found that the VHA formulary transition from budesonide-formoterol metered-dose inhaler to fluticasone-salmeterol dry-powder inhaler was associated with increased health care utilization, suggesting potential harm and the need to reevaluate this policy change.

BACKGROUND: The incidence of adverse events and desaturation during airway-securing procedures (a sequence from preoxygenation to completion of tracheal intubation or supraglottic airway placement) under general anesthesia in children remains underexplored. Thus, this study investigated the incidence of adverse and desaturation events and associated risk factors. METHODS: This was a prospective, multicenter, observational study conducted between June 2022 and January 2024 in 10 tertiary care (6 pediatric and 4 university [mixed adult-pediatric]) hospitals in Japan. A standardized data collection system was applied through the recruited institutions to collect 95% or more of cases. The primary and secondary outcomes were adverse events and a 10% or greater drop in oxygen saturation (desaturation) associated with airway-securing procedures. RESULTS: There were 17,007 airway management procedures in 16,695 children (mean ± SD age, 6.3 ± 4.8 yr). Any adverse events occurred in 346 of 17,007 (2.0%; 95% CI, 1.8 to 2.3) children, including 189 of 17,007 (1.1%; 0.96 to 1.3) respiratory adverse events. Desaturation occurred during 395 of 17,007 (2.3%; 2.1 to 2.6) procedures, with 66 of 308 (21.4%; 17.0 to 26.4) in neonates and 210 of 2,298 (9.1%; 8.0 to 10.4) in infants. Multilevel regression analysis showed younger age (adjusted odds ratio, 0.92; 95% CI, 0.90 to 0.95; P < 0.001), airway management in radiation diagnostic/therapy rooms (5.7, 1.64 to 19.9; P = 0.006), airway sensitivity (1.46, 1.09 to 1.94; P = 0.010), craniocervical surgery (1.41, 1.09 to 1.83; P = 0.009), and presence of one anatomical difficult airway feature (1.74, 1.02 to 2.95; P = 0.042) versus two or more anatomic difficult airway features (2.82, 1.21 to 6.6; P = 0.017) as risk factors of any adverse events. Supraglottic airway device usage at the first attempt (0.42, 0.288 to 0.62; P < 0.001) and muscle relaxant administration (0.62, 0.43 to 0.89; P = 0.009) showed beneficial effects. CONCLUSION: s: The Japan Pediatric Difficult Airway in Anesthesia (J-PEDIA) study demonstrated adverse event and desaturation incidences and the impact of clinically relevant risk factors during airway-securing procedures in Asian children. This study can help anesthesiologists to identify high-risk children and create a safe airway-securing strategy.