Inhaled Fluticasone Furoate for Outpatient Treatment of Covid-19.

BACKGROUND: The effectiveness of inhaled glucocorticoids in shortening the time to symptom resolution or preventing hospitalization or death among outpatients with mild-to-moderate coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a decentralized, double-blind, randomized, placebo-controlled platform trial in the United States to assess the use of repurposed medications in outpatients with confirmed coronavirus disease 2019 (Covid-19). Nonhospitalized adults 30 years of age or older who had at least two symptoms of acute infection that had been present for no more than 7 days before enrollment were randomly assigned to receive inhaled fluticasone furoate at a dose of 200 µg once daily for 14 days or placebo. The primary outcome was the time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Key secondary outcomes included hospitalization or death by day 28 and a composite outcome of the need for an urgent-care or emergency department visit or hospitalization or death through day 28. RESULTS: Of the 1407 enrolled participants who underwent randomization, 715 were assigned to receive inhaled fluticasone furoate and 692 to receive placebo, and 656 and 621, respectively, were included in the analysis. There was no evidence that the use of fluticasone furoate resulted in a shorter time to recovery than placebo (hazard ratio, 1.01; 95% credible interval, 0.91 to 1.12; posterior probability of benefit [defined as a hazard ratio >1], 0.56). A total of 24 participants (3.7%) in the fluticasone furoate group had urgent-care or emergency department visits or were hospitalized, as compared with 13 participants (2.1%) in the placebo group (hazard ratio, 1.9; 95% credible interval, 0.8 to 3.5). Three participants in each group were hospitalized, and no deaths occurred. Adverse events were uncommon in both groups. CONCLUSIONS: Treatment with inhaled fluticasone furoate for 14 days did not result in a shorter time to recovery than placebo among outpatients with Covid-19 in the United States. (Funded by the National Center for Advancing Translational Sciences and others; ACTIV-6 ClinicalTrials.gov number, NCT04885530.).

Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension.

BACKGROUND: Intravenous fluids and vasopressor agents are commonly used in early resuscitation of patients with sepsis, but comparative data for prioritizing their delivery are limited. METHODS: In an unblinded superiority trial conducted at 60 U.S. centers, we randomly assigned patients to either a restrictive fluid strategy (prioritizing vasopressors and lower intravenous fluid volumes) or a liberal fluid strategy (prioritizing higher volumes of intravenous fluids before vasopressor use) for a 24-hour period. Randomization occurred within 4 hours after a patient met the criteria for sepsis-induced hypotension refractory to initial treatment with 1 to 3 liters of intravenous fluid. We hypothesized that all-cause mortality before discharge home by day 90 (primary outcome) would be lower with a restrictive fluid strategy than with a liberal fluid strategy. Safety was also assessed. RESULTS: A total of 1563 patients were enrolled, with 782 assigned to the restrictive fluid group and 781 to the liberal fluid group. Resuscitation therapies that were administered during the 24-hour protocol period differed between the two groups; less intravenous fluid was administered in the restrictive fluid group than in the liberal fluid group (difference of medians, -2134 ml; 95% confidence interval [CI], -2318 to -1949), whereas the restrictive fluid group had earlier, more prevalent, and longer duration of vasopressor use. Death from any cause before discharge home by day 90 occurred in 109 patients (14.0%) in the restrictive fluid group and in 116 patients (14.9%) in the liberal fluid group (estimated difference, -0.9 percentage points; 95% CI, -4.4 to 2.6; P = 0.61); 5 patients in the restrictive fluid group and 4 patients in the liberal fluid group had their data censored (lost to follow-up). The number of reported serious adverse events was similar in the two groups. CONCLUSIONS: Among patients with sepsis-induced hypotension, the restrictive fluid strategy that was used in this trial did not result in significantly lower (or higher) mortality before discharge home by day 90 than the liberal fluid strategy. (Funded by the National Heart, Lung, and Blood Institute; CLOVERS ClinicalTrials.gov number, NCT03434028.).

Video versus Direct Laryngoscopy for Tracheal Intubation of Critically Ill Adults.

BACKGROUND: Whether video laryngoscopy as compared with direct laryngoscopy increases the likelihood of successful tracheal intubation on the first attempt among critically ill adults is uncertain. METHODS: In a multicenter, randomized trial conducted at 17 emergency departments and intensive care units (ICUs), we randomly assigned critically ill adults undergoing tracheal intubation to the video-laryngoscope group or the direct-laryngoscope group. The primary outcome was successful intubation on the first attempt. The secondary outcome was the occurrence of severe complications during intubation; severe complications were defined as severe hypoxemia, severe hypotension, new or increased vasopressor use, cardiac arrest, or death. RESULTS: The trial was stopped for efficacy at the time of the single preplanned interim analysis. Among 1417 patients who were included in the final analysis (91.5% of whom underwent intubation that was performed by an emergency medicine resident or a critical care fellow), successful intubation on the first attempt occurred in 600 of the 705 patients (85.1%) in the video-laryngoscope group and in 504 of the 712 patients (70.8%) in the direct-laryngoscope group (absolute risk difference, 14.3 percentage points; 95% confidence interval [CI], 9.9 to 18.7; P<0.001). A total of 151 patients (21.4%) in the video-laryngoscope group and 149 patients (20.9%) in the direct-laryngoscope group had a severe complication during intubation (absolute risk difference, 0.5 percentage points; 95% CI, -3.9 to 4.9). Safety outcomes, including esophageal intubation, injury to the teeth, and aspiration, were similar in the two groups. CONCLUSIONS: Among critically ill adults undergoing tracheal intubation in an emergency department or ICU, the use of a video laryngoscope resulted in a higher incidence of successful intubation on the first attempt than the use of a direct laryngoscope. (Funded by the U.S. Department of Defense; DEVICE ClinicalTrials.gov number, NCT05239195.).

Early Remdesivir to Prevent Progression to Severe Covid-19 in Outpatients.

BACKGROUND: Remdesivir improves clinical outcomes in patients hospitalized with moderate-to-severe coronavirus disease 2019 (Covid-19). Whether the use of remdesivir in symptomatic, nonhospitalized patients with Covid-19 who are at high risk for disease progression prevents hospitalization is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving nonhospitalized patients with Covid-19 who had symptom onset within the previous 7 days and who had at least one risk factor for disease progression (age ≥60 years, obesity, or certain coexisting medical conditions). Patients were randomly assigned to receive intravenous remdesivir (200 mg on day 1 and 100 mg on days 2 and 3) or placebo. The primary efficacy end point was a composite of Covid-19-related hospitalization or death from any cause by day 28. The primary safety end point was any adverse event. A secondary end point was a composite of a Covid-19-related medically attended visit or death from any cause by day 28. RESULTS: A total of 562 patients who underwent randomization and received at least one dose of remdesivir or placebo were included in the analyses: 279 patients in the remdesivir group and 283 in the placebo group. The mean age was 50 years, 47.9% of the patients were women, and 41.8% were Hispanic or Latinx. The most common coexisting conditions were diabetes mellitus (61.6%), obesity (55.2%), and hypertension (47.7%). Covid-19-related hospitalization or death from any cause occurred in 2 patients (0.7%) in the remdesivir group and in 15 (5.3%) in the placebo group (hazard ratio, 0.13; 95% confidence interval [CI], 0.03 to 0.59; P = 0.008). A total of 4 of 246 patients (1.6%) in the remdesivir group and 21 of 252 (8.3%) in the placebo group had a Covid-19-related medically attended visit by day 28 (hazard ratio, 0.19; 95% CI, 0.07 to 0.56). No patients had died by day 28. Adverse events occurred in 42.3% of the patients in the remdesivir group and in 46.3% of those in the placebo group. CONCLUSIONS: Among nonhospitalized patients who were at high risk for Covid-19 progression, a 3-day course of remdesivir had an acceptable safety profile and resulted in an 87% lower risk of hospitalization or death than placebo. (Funded by Gilead Sciences; PINETREE ClinicalTrials.gov number, NCT04501952; EudraCT number, 2020-003510-12.).

Effectiveness of the original monovalent mRNA COVID-19 vaccination series against hospitalization for COVID-19-associated venous thromboembolism.

BACKGROUND: COVID-19 is a strong risk factor for venous thromboembolism (VTE). Few studies have evaluated the effectiveness of COVID-19 vaccination in preventing hospitalization for COVID-19 with VTE. METHODS: Adults hospitalized at 21 sites between March 2021 and October 2022 with symptoms of acute respiratory illness were assessed for COVID-19, completion of the original monovalent mRNA COVID-19 vaccination series, and VTE. Prevalence of VTE was compared between unvaccinated and vaccinated patients with COVID-19. Vaccine effectiveness in preventing COVID-19 hospitalization with VTE was calculated using a test negative design. Vaccine effectiveness was also stratified by predominant circulating SARS-CoV-2 variant. RESULTS: Among 18,811 patients (median age 63 [IQR:50-73], 49% women, 59% non-Hispanic White, 20% non-Hispanic Black, 14% Hispanic, and median of 2 comorbid conditions [IQR:1-3]), 9,792 were admitted with COVID-19 (44% vaccinated) and 9,019 were test-negative controls (73% vaccinated). Among patients with COVID-19, 601 were diagnosed with VTE by hospital day 28, of whom 170 were vaccinated. VTE was more common among unvaccinated than vaccinated COVID-19 patients (7.8% versus 4.0%; p=0.001). Vaccine effectiveness against COVID-19 hospitalization with VTE was 84% (95% CI: 80-87%) overall. Vaccine effectiveness stratified by predominant circulating variant was 88% (73-95%) for alpha, 93% (90-95%) for delta, and 68% (58-76%) for omicron variants. CONCLUSIONS AND RELEVANCE: Vaccination with the original monovalent mRNA series was associated with a decrease in COVID-19 hospitalization with VTE, though data detailing prior history of VTE and use of anticoagulation were not available. These findings will inform risk-benefit considerations for those considering vaccination.

Evaluation of the feasibility and efficacy of point-of-care antibody tests for biomarker guided management of COVID-19.

BACKGROUND: Biomarker guided therapy could improve management of COVID-19 inpatients. Although some results indicate that antibody tests are prognostic, little is known about patient management using point-of-care (POC) antibody tests. METHODS: COVID-19 inpatients were recruited to evaluate 2 POC tests: LumiraDX and RightSign. Ease of use data was collected. Blood was also collected for centralized testing using established antibody assays (GenScript cPass). A nested case-control study assessed if POC tests conducted on stored specimens were predictive of time to sustained recovery, mortality, and a composite safety outcome. RESULTS: While both POC tests exhibited moderate agreement with the GenScript assay (both agreeing with 89% of antibody determinations), they were significantly different from the GenScript assay. Treating the GenScript assay as the gold standard, the LumiraDX assay had 99.5% sensitivity and 58.1% specificity while the RightSign assay had 89.5% sensitivity and 84.0% specificity. The LumiraDX assay frequently gave indeterminant results. Both tests were significantly associated with clinical outcomes. CONCLUSIONS: Although both POC tests deviated moderately from the GenScript assay, they predicted outcomes of interest. The RightSign test was easier to use and was more likely to detect those lacking antibody compared to the LumiraDX test treating GenScript as the gold standard.

Viral and Host Factors Are Associated With Mortality in Hospitalized Patients With COVID-19.

BACKGROUND: Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. METHODS: A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. RESULTS: Viral Ag ≥4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], ≥35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; ≥4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs ≤5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. CONCLUSIONS: Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.

Vaccine Effectiveness Against Influenza A-Associated Hospitalization, Organ Failure, and Death: United States, 2022-2023.

BACKGROUND: Influenza circulation during the 2022-2023 season in the United States largely returned to pre-coronavirus disease 2019 (COVID-19)-pandemic patterns and levels. Influenza A(H3N2) viruses were detected most frequently this season, predominately clade 3C.2a1b.2a, a close antigenic match to the vaccine strain. METHODS: To understand effectiveness of the 2022-2023 influenza vaccine against influenza-associated hospitalization, organ failure, and death, a multicenter sentinel surveillance network in the United States prospectively enrolled adults hospitalized with acute respiratory illness between 1 October 2022, and 28 February 2023. Using the test-negative design, vaccine effectiveness (VE) estimates against influenza-associated hospitalization, organ failures, and death were measured by comparing the odds of current-season influenza vaccination in influenza-positive case-patients and influenza-negative, SARS-CoV-2-negative control-patients. RESULTS: A total of 3707 patients, including 714 influenza cases (33% vaccinated) and 2993 influenza- and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-negative controls (49% vaccinated) were analyzed. VE against influenza-associated hospitalization was 37% (95% confidence interval [CI]: 27%-46%) and varied by age (18-64 years: 47% [30%-60%]; ≥65 years: 28% [10%-43%]), and virus (A[H3N2]: 29% [6%-46%], A[H1N1]: 47% [23%-64%]). VE against more severe influenza-associated outcomes included: 41% (29%-50%) against influenza with hypoxemia treated with supplemental oxygen; 65% (56%-72%) against influenza with respiratory, cardiovascular, or renal failure treated with organ support; and 66% (40%-81%) against influenza with respiratory failure treated with invasive mechanical ventilation. CONCLUSIONS: During an early 2022-2023 influenza season with a well-matched influenza vaccine, vaccination was associated with reduced risk of influenza-associated hospitalization and organ failure.

Effectiveness of Updated 2023-2024 (Monovalent XBB.1.5) COVID-19 Vaccination Against SARS-CoV-2 Omicron XBB and BA.2.86/JN.1 Lineage Hospitalization and a Comparison of Clinical Severity-IVY Network, 26 Hospitals, October 18, 2023-March 9, 2024.

BACKGROUND: Assessing variant-specific COVID-19 vaccine effectiveness (VE) and severity can inform public health risk assessments and decisions about vaccine composition. BA.2.86 and its descendants, including JN.1 (referred to collectively as "JN lineages"), emerged in late 2023 and exhibited substantial divergence from co-circulating XBB lineages. METHODS: We analyzed patients hospitalized with COVID-19-like illness at 26 hospitals in 20 U.S. states admitted October 18, 2023-March 9, 2024. Using a test-negative, case-control design, we estimated effectiveness of an updated 2023-2024 (Monovalent XBB.1.5) COVID-19 vaccine dose against sequence-confirmed XBB and JN lineage hospitalization using logistic regression. Odds of severe outcomes, including intensive care unit (ICU) admission and invasive mechanical ventilation (IMV) or death, were compared for JN versus XBB lineage hospitalizations using logistic regression. RESULTS: 585 case-patients with XBB lineages, 397 case-patients with JN lineages, and 4,580 control-patients were included. VE in the first 7-89 days after receipt of an updated dose was 54.2% (95% CI = 36.1%-67.1%) against XBB lineage hospitalization and 32.7% (95% CI = 1.9%-53.8%) against JN lineage hospitalization. Odds of ICU admission (adjusted odds ratio [aOR] 0.80; 95% CI = 0.46-1.38) and IMV or death (aOR 0.69; 95% CI = 0.34-1.40) were not significantly different among JN compared to XBB lineage hospitalizations. CONCLUSIONS: Updated 2023-2024 COVID-19 vaccination provided protection against both XBB and JN lineage hospitalization, but protection against the latter may be attenuated by immune escape. Clinical severity of JN lineage hospitalizations was not higher relative to XBB.

A Neutralizing Monoclonal Antibody for Hospitalized Patients with Covid-19.

BACKGROUND: LY-CoV555, a neutralizing monoclonal antibody, has been associated with a decrease in viral load and the frequency of hospitalizations or emergency department visits among outpatients with coronavirus disease 2019 (Covid-19). Data are needed on the effect of this antibody in patients who are hospitalized with Covid-19. METHODS: In this platform trial of therapeutic agents, we randomly assigned hospitalized patients who had Covid-19 without end-organ failure in a 1:1 ratio to receive either LY-CoV555 or matching placebo. In addition, all the patients received high-quality supportive care as background therapy, including the antiviral drug remdesivir and, when indicated, supplemental oxygen and glucocorticoids. LY-CoV555 (at a dose of 7000 mg) or placebo was administered as a single intravenous infusion over a 1-hour period. The primary outcome was a sustained recovery during a 90-day period, as assessed in a time-to-event analysis. An interim futility assessment was performed on the basis of a seven-category ordinal scale for pulmonary function on day 5. RESULTS: On October 26, 2020, the data and safety monitoring board recommended stopping enrollment for futility after 314 patients (163 in the LY-CoV555 group and 151 in the placebo group) had undergone randomization and infusion. The median interval since the onset of symptoms was 7 days (interquartile range, 5 to 9). At day 5, a total of 81 patients (50%) in the LY-CoV555 group and 81 (54%) in the placebo group were in one of the two most favorable categories of the pulmonary outcome. Across the seven categories, the odds ratio of being in a more favorable category in the LY-CoV555 group than in the placebo group was 0.85 (95% confidence interval [CI], 0.56 to 1.29; P = 0.45). The percentage of patients with the primary safety outcome (a composite of death, serious adverse events, or clinical grade 3 or 4 adverse events through day 5) was similar in the LY-CoV555 group and the placebo group (19% and 14%, respectively; odds ratio, 1.56; 95% CI, 0.78 to 3.10; P = 0.20). The rate ratio for a sustained recovery was 1.06 (95% CI, 0.77 to 1.47). CONCLUSIONS: Monoclonal antibody LY-CoV555, when coadministered with remdesivir, did not demonstrate efficacy among hospitalized patients who had Covid-19 without end-organ failure. (Funded by Operation Warp Speed and others; TICO ClinicalTrials.gov number, NCT04501978.).

Association between monoclonal antibody therapy, vaccination, and longer-term symptom resolution after acute COVID-19.

Effective therapies for reducing post-acute sequelae of COVID-19 (PASC) symptoms are lacking. Evaluate the association between monoclonal antibody (mAb) treatment or COVID-19 vaccination with symptom recovery in COVID-19 participants. The longitudinal survey-based cohort study was conducted from April 2021 to January 2022 across a multihospital Colorado health system. Adults ≥18 years with a positive SARS-CoV-2 test were included. Primary exposures were mAb treatment and COVID-19 vaccination. The primary outcome was time to symptom resolution after SARS-CoV-2 positive test date. The secondary outcome was hospitalization within 28 days of a positive SARS-CoV-2 test. Analysis included 1612 participants, 539 mAb treated, and 486 with ≥2 vaccinations. Time to symptom resolution was similar between mAb treated versus untreated patients (adjusted hazard ratio (aHR): 0.90, 95% CI: 0.77-1.04). Time to symptom resolution was shorter for patients who received ≥2 vaccinations compared to those unvaccinated (aHR: 1.56, 95% CI: 1.31-1.88). 28-day hospitalization risk was lower for patients receiving mAb therapy (adjusted odds ratio [aOR]: 0.31, 95% CI: 0.19-0.50) and ≥2 vaccinations (aOR: 0.33, 95% CI: 0.20-0.55), compared with untreated or unvaccinated status. Analysis included 1612 participants, 539 mAb treated, and 486 with ≥2 vaccinations. Time to symptom resolution was similar between mAb treated versus untreated patients (adjusted hazard ratio (aHR): 0.90, 95% CI: 0.77-1.04). Time to symptom resolution was shorter for patients who received ≥2 vaccinations compared to those unvaccinated (aHR: 1.56, 95% CI: 1.31-1.88). 28-day hospitalization risk was lower for patients receiving mAb therapy (adjusted odds ratio [aOR]: 0.31, 95% CI: 0.19-0.50) and ≥2 vaccinations (aOR: 0.33, 95% CI: 0.20-0.55), compared with untreated or unvaccinated status. COVID-19 vaccination, but not mAb therapy, was associated with a shorter time to symptom resolution. Both were associated with lower 28-day hospitalization.

A prospective, pragmatic non-inferiority study of emergency intubation success with the single-use i-view versus standard reusable video laryngoscope.

INTRODUCTION: Video laryngoscope (VL) technology improves first-pass success. The novel i-view VL device is inexpensive and disposable. We sought to determine the first-pass intubation success with the i-view VL device versus the standard reusable VL systems in routine use at each site. METHODS: We performed a prospective, pragmatic study at two major emergency departments (EDs) when VL was used. We rotated i-view versus reusable VL as the preferred device of the month based on an a priori schedule. An investigator-initiated interim analysis was performed. Our primary outcome was a first-pass success with a non-inferiority margin of 10% based on the per-protocol analysis. RESULTS: There were 93 intubations using the reusable VL devices and 81 intubations using the i-view. Our study was stopped early due to futility in reaching our predetermined non-inferiority margin. Operator and patient characteristics were similar between the two groups. The first-pass success rate for the i-view group was 69.1% compared to 84.3% for the reusable VL group. A non-inferiority analysis indicated that the difference (-15.1%) and corresponding 90% confidence limits (-25.3% to -5.0%) did not fall within the predetermined 10% non-inferiority margin. CONCLUSIONS: The i-view device failed to meet our predetermined non-inferiority margin when compared to the reusable VL systems with the study stopping early due to futility. Significant crossover occurred at the discretion of the intubating operator during the i-view month.

Interim Effectiveness of Updated 2023-2024 (Monovalent XBB.1.5) COVID-19 Vaccines Against COVID-19-Associated Emergency Department and Urgent Care Encounters and Hospitalization Among Immunocompetent Adults Aged ≥18 Years - VISION and IVY Networks, September 2023-January 2024.

In September 2023, CDC's Advisory Committee on Immunization Practices recommended updated 2023-2024 (monovalent XBB.1.5) COVID-19 vaccination for all persons aged ≥6 months to prevent COVID-19, including severe disease. However, few estimates of updated vaccine effectiveness (VE) against medically attended illness are available. This analysis evaluated VE of an updated COVID-19 vaccine dose against COVID-19-associated emergency department (ED) or urgent care (UC) encounters and hospitalization among immunocompetent adults aged ≥18 years during September 2023-January 2024 using a test-negative, case-control design with data from two CDC VE networks. VE against COVID-19-associated ED/UC encounters was 51% (95% CI = 47%-54%) during the first 7-59 days after an updated dose and 39% (95% CI = 33%-45%) during the 60-119 days after an updated dose. VE estimates against COVID-19-associated hospitalization from two CDC VE networks were 52% (95% CI = 47%-57%) and 43% (95% CI = 27%-56%), with a median interval from updated dose of 42 and 47 days, respectively. Updated COVID-19 vaccine provided increased protection against COVID-19-associated ED/UC encounters and hospitalization among immunocompetent adults. These results support CDC recommendations for updated 2023-2024 COVID-19 vaccination. All persons aged ≥6 months should receive updated 2023-2024 COVID-19 vaccine.

Interim Estimates of 2023-24 Seasonal Influenza Vaccine Effectiveness - United States.

In the United States, annual influenza vaccination is recommended for all persons aged ≥6 months. Using data from four vaccine effectiveness (VE) networks during the 2023-24 influenza season, interim influenza VE was estimated among patients aged ≥6 months with acute respiratory illness-associated medical encounters using a test-negative case-control study design. Among children and adolescents aged 6 months-17 years, VE against influenza-associated outpatient visits ranged from 59% to 67% and against influenza-associated hospitalization ranged from 52% to 61%. Among adults aged ≥18 years, VE against influenza-associated outpatient visits ranged from 33% to 49% and against hospitalization from 41% to 44%. VE against influenza A ranged from 46% to 59% for children and adolescents and from 27% to 46% for adults across settings. VE against influenza B ranged from 64% to 89% for pediatric patients in outpatient settings and from 60% to 78% for all adults across settings. These findings demonstrate that the 2023-24 seasonal influenza vaccine is effective at reducing the risk for medically attended influenza virus infection. CDC recommends that all persons aged ≥6 months who have not yet been vaccinated this season get vaccinated while influenza circulates locally.

Association Between Neuromuscular Blocking Agents and Outcomes of Emergency Tracheal Intubation: A Secondary Analysis of Randomized Trials.

STUDY OBJECTIVE: To examine the association between the neuromuscular blocking agent received (succinylcholine versus rocuronium) and the incidences of successful intubation on the first attempt and severe complications during tracheal intubation of critically ill adults in an emergency department (ED) or ICU. METHODS: We performed a secondary analysis of data from 2 multicenter randomized trials in critically ill adults undergoing tracheal intubation in an ED or ICU. Using a generalized linear mixed-effects model with prespecified baseline covariates, we examined the association between the neuromuscular blocking agent received (succinylcholine versus rocuronium) and the incidences of successful intubation on the first attempt (primary outcome) and severe complications during tracheal intubation (secondary outcome). RESULTS: Among the 2,440 patients in the trial data sets, 2,339 (95.9%) were included in the current analysis; 475 patients (20.3%) received succinylcholine and 1,864 patients (79.7%) received rocuronium. Successful intubation on the first attempt occurred in 375 patients (78.9%) who received succinylcholine and 1,510 patients (81.0%) who received rocuronium (an adjusted odds ratio of 0.87; 95% CI 0.65 to 1.15). Severe complications occurred in 67 patients (14.1%) who received succinylcholine and 456 patients (24.5%) who received rocuronium (adjusted odds ratio, 0.88; 95% CI 0.62 to 1.26). CONCLUSION: Among critically ill adults undergoing tracheal intubation, the incidences of successful intubation on the first attempt and severe complications were not significantly different between patients who received succinylcholine and patients who received rocuronium.

Real-world evaluation of early remdesivir in high-risk COVID-19 outpatients during Omicron including BQ.1/BQ.1.1/XBB.1.5.

BACKGROUND: A trial performed among unvaccinated, high-risk outpatients with COVID-19 during the delta period showed remdesivir reduced hospitalization. We used our real-world data platform to determine the effectiveness of remdesivir on reducing 28-day hospitalization among outpatients with mild-moderate COVID-19 during an Omicron period including BQ.1/BQ.1.1/XBB.1.5. METHODS: We did a propensity-matched, retrospective cohort study of non-hospitalized adults with SARS-CoV-2 infection between April 7, 2022, and February 7, 2023. Electronic healthcare record data from a large health system in Colorado were linked to statewide vaccination and mortality data. We included patients with a positive SARS-CoV-2 test or outpatient remdesivir administration. Exclusion criteria were other SARS-CoV-2 treatments or positive SARS-CoV-2 test more than seven days before remdesivir. The primary outcome was all-cause hospitalization up to day 28. Secondary outcomes included 28-day COVID-related hospitalization and 28-day all-cause mortality. RESULTS: Among 29,270 patients with SARS-CoV-2 infection, 1,252 remdesivir-treated patients were matched to 2,499 untreated patients. Remdesivir was associated with lower 28-day all-cause hospitalization (1.3% vs. 3.3%, adjusted hazard ratio (aHR) 0.39 [95% CI 0.23-0.67], p < 0.001) than no treatment. All-cause mortality at 28 days was numerically lower among remdesivir-treated patients (0.1% vs. 0.4%; aOR 0.32 [95% CI 0.03-1.40]). Similar benefit of RDV treatment on 28-day all-cause hospitalization was observed across Omicron periods, aOR (95% CI): BA.2/BA2.12.1 (0.77[0.19-2.41]), BA.4/5 (0.50[95% CI 0.50-1.01]), BQ.1/BQ.1.1/XBB.1.5 (0.21[95% CI 0.08-0.57]. CONCLUSION: Among outpatients with SARS-CoV-2 during recent Omicron surges, remdesivir was associated with lower hospitalization than no treatment, supporting current National Institutes of Health Guidelines.

Individualized Treatment Effects of Bougie versus Stylet for Tracheal Intubation in Critical Illness.

Rationale: A recent randomized trial found that using a bougie did not increase the incidence of successful intubation on first attempt in critically ill adults. The average effect of treatment in a trial population, however, may differ from effects for individuals. Objective: We hypothesized that application of a machine learning model to data from a clinical trial could estimate the effect of treatment (bougie vs. stylet) for individual patients based on their baseline characteristics ("individualized treatment effects"). Methods: This was a secondary analysis of the BOUGIE (Bougie or Stylet in Patients Undergoing Intubation Emergently) trial. A causal forest algorithm was used to model differences in outcome probabilities by randomized group assignment (bougie vs. stylet) for each patient in the first half of the trial (training cohort). This model was used to predict individualized treatment effects for each patient in the second half (validation cohort). Measurements and Main Results: Of 1,102 patients in the BOUGIE trial, 558 (50.6%) were the training cohort, and 544 (49.4%) were the validation cohort. In the validation cohort, individualized treatment effects predicted by the model significantly modified the effect of trial group assignment on the primary outcome (P value for interaction = 0.02; adjusted qini coefficient, 2.46). The most important model variables were difficult airway characteristics, body mass index, and Acute Physiology and Chronic Health Evaluation II score. Conclusions: In this hypothesis-generating secondary analysis of a randomized trial with no average treatment effect and no treatment effect in any prespecified subgroups, a causal forest machine learning algorithm identified patients who appeared to benefit from the use of a bougie over a stylet and from the use of a stylet over a bougie using complex interactions between baseline patient and operator characteristics.

Interventions associated with survival after prehospital intubation in the deployed combat setting.

INTRODUCTION: Airway compromise is the second leading cause of potentially preventable death on the battlefield. Prehospital airway management is often unavoidable in a kinetic combat environment and expected to increase in future wars where timely evacuation will be unreliable and air superiority not guaranteed. We compared characteristics of survivors to non-survivors among combat casualties undergoing prehospital airway intubation. MATERIALS AND METHODS: We requested all Department of Defense Trauma Registry (DODTR) encounters during 2007-2023 with documentation of any airway intervention or assessment within the first 72-h after injury. We conducted a retrospective cohort study of all casualties with intubation documented in the prehospital setting. We used descriptive and inferential statistical analysis to compare survivors through 7 days post injury versus non-survivors. We constructed 3 multivariable logistic regression models to test for associations between interventions and 7-day survival after adjusting for injury severity score, mechanism of injury, and receipt of sedatives, paralytics, and blood products. RESULTS: There were 1377 of 48,301 patients with documentation of prehospital intubation in a combat setting. Of these, 1028 (75%) survived through 7 days post injury. Higher proportions of survivors received ketamine, paralytic agents, parenteral opioids, and parenteral benzodiazepines; there was no difference in the proportions of survivors versus non-survivors receiving etomidate. The multivariable models consistently demonstrated positive associations between 7-day survival and receipt of non-depolarizing paralytics and opioid analgesics. CONCLUSIONS: We found an association between non-depolarizing paralytic and opioid receipt with 7-day survival among patients undergoing prehospital intubation. The literature would benefit from future multi-center randomized controlled trials to establish optimal pharmacologic strategies for trauma patients undergoing prehospital intubation.

Association between multiple intubation attempts and complications during emergency department airway management: A national emergency airway registry study.

OBJECTIVE: Peri-intubation complications are important sequelae of airway management in the emergency department (ED). Our objective was to quantify the increased risk of complications with multiple attempts at emergency airway intubation in the ED. METHODS: This is a secondary analysis of a prospectively collected multicenter registry (National Emergency Airway Registry) consisting of attempted ED intubations among subjects aged >14 years. The primary exposure variable was the number of intubation attempts. The primary outcome measure was the occurrence of peri-intubation major complications within 15 min of intubation including hypotension, hypoxemia, vomiting, dysrhythmias, cardiac arrest, esophageal intubation, and failed airway with cricothyrotomy. We constructed multivariable logistic regression models to determine the associations between complications and the number of intubation attempts while controlling for measured pre-exposure variables. RESULTS: There were 19,071 intubations in the NEAR database, of which 15,079 met inclusion for this analysis. Of these, 13,459 were successfully intubated on the first attempt, 1,268 on the second attempt, 269 on the third attempt, 61 on the fourth attempt, and 22 on the fifth or more attempt. A complication occurred in 2,137 encounters (14 %). Major complications accompanied 1,968 encounters (13 %) whereas minor complications affected 315 encounters (2 %). The most common major complication was hypoxia. In our multivariable logistic regression model, odds ratios with 95 % confidence intervals for the occurrence of major complications for multiple attempts compared to first-pass success were 4.4 (3.6-5.3), 7.4 (5.0-10.7), 13.9 (5.6-34.3), and 9.3 (2.1-41.7) for attempts 2-5+ (reference attempt 1), respectively. CONCLUSIONS: We found an independent association between the number of intubation attempts among ED patients undergoing emergency airway intubation and the risk of complications.

Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis: The ASTER Randomized Clinical Trial.

Importance: Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates. Objective: To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo. Design, Setting, and Participants: Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation. Intervention: Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days. Main Outcome and Measures: The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL. Results: Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, -1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, -6.3; 95% CI, -10.8 to -1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen. Conclusions and Relevance: Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04291508.