Tackling Brain and Muscle Dysfunction in Acute Respiratory Distress Syndrome Survivors: National Heart, Lung, and Blood Institute Workshop Report.

Acute respiratory distress syndrome (ARDS) is associated with long-term impairments in brain and muscle function that significantly impact the quality of life of those who survive the acute illness. The mechanisms underlying these impairments are not yet well understood, and evidence-based interventions to minimize the burden on patients remain unproven. The National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health assembled a workshop in April 2023 to review the state of the science regarding ARDS-associated brain and muscle dysfunction, to identify gaps in current knowledge, and to determine priorities for future investigation. The workshop included presentations by scientific leaders across the translational science spectrum and was open to the public as well as the scientific community. This report describes the themes discussed at the workshop as well as recommendations to advance the field toward the goal of improving the health and wellbeing of ARDS survivors.

Validation of a Novel, Rapid Sepsis Diagnostic for Emergency Department Use.

OBJECTIVES: To assess the in vitro IntelliSep test, a microfluidic assay that quantifies the state of immune activation by evaluating the biophysical properties of leukocytes, as a rapid diagnostic for sepsis. DESIGN: Prospective cohort study. SETTING: Five emergency departments (EDs) in Louisiana, Missouri, North Carolina, and Washington. PATIENTS: Adult patients presenting to the ED with signs (two of four Systemic Inflammatory Response Syndrome criteria, where one must be temperature or WBC count) or suspicion (provider-ordered culture) of infection. INTERVENTIONS: All patients underwent testing with the IntelliSep using ethylene diamine tetraacetic acid-anticoagulated whole blood followed by retrospective adjudication for sepsis by sepsis-3 criteria by a blinded panel of physicians. MEASUREMENTS AND MAIN RESULTS: Of 599 patients enrolled, 572 patients were included in the final analysis. The result of the IntelliSep test is reported as the IntelliSep Index (ISI), ranging from 0.1 to 10.0, divided into three interpretation bands for the risk of sepsis: band 1 (low) to band 3 (high). The median turnaround time for ISI results was 7.2 minutes. The ISI resulted band 1 in 252 (44.1%), band 2 in 160 (28.0%), and band 3 in 160 (28.0%). Sepsis occurred in 26.6% (152 of 572 patients). Sepsis prevalence was 11.1% (95% CI, 7.5-15.7%) in band 1, 28.1% (95% CI, 21.3-35.8%) in band 2, and 49.4% (95% CI, 41.4-57.4%) in band 3. The Positive Percent Agreement of band 1 was 81.6% and the Negative Percent Agreement of band 3 was 80.7%, with an area under the receiver operating characteristic curve of 0.74. Compared with band 1, band 3 correlated with adverse clinical outcomes, including mortality, and resource utilization. CONCLUSIONS: Increasing ISI interpretation band is associated with increasing probability of sepsis in patients presenting to the ED with suspected infection.

Identification and Management of Acute Neuromuscular Respiratory Failure in the ICU.

Respiratory failure is a common and potentially life-threatening complication of neuromuscular diseases. Prompt recognition and accurate diagnosis of new or worsening chronic neuromuscular disease have important clinical management and prognostic implications. In this article, we present an approach to the acute presentation of undifferentiated neuromuscular respiratory failure in the ICU and guidance for determination and respiratory management of the underlying disorder.

Early Serial Echocardiographic and Ultrasonographic Findings in Critically Ill Patients With COVID-19.

Background: Cardiac function of critically ill patients with COVID-19 generally has been reported from clinically obtained data. Echocardiographic deformation imaging can identify ventricular dysfunction missed by traditional echocardiographic assessment. Research Question: What is the prevalence of ventricular dysfunction and what are its implications for the natural history of critical COVID-19? Study Design and Methods: This is a multicenter prospective cohort of critically ill patients with COVID-19. We performed serial echocardiography and lower extremity vascular ultrasound on hospitalization days 1, 3, and 8. We defined left ventricular (LV) dysfunction as the absolute value of longitudinal strain of < 17% or left ventricle ejection fraction (LVEF) of < 50%. Primary clinical outcome was inpatient survival. Results: We enrolled 110 patients. Thirty-nine (35.5%) died before hospital discharge. LV dysfunction was present at admission in 38 patients (34.5%) and in 21 patients (36.2%) on day 8 (P = .59). Median baseline LVEF was 62% (interquartile range [IQR], 52%-69%), whereas median absolute value of baseline LV strain was 16% (IQR, 14%-19%). Survivors and nonsurvivors did not differ statistically significantly with respect to day 1 LV strain (17.9% vs 14.4%; P = .12) or day 1 LVEF (60.5% vs 65%; P = .06). Nonsurvivors showed worse day 1 right ventricle (RV) strain than survivors (16.3% vs 21.2%; P = .04). Interpretation: Among patients with critical COVID-19, LV and RV dysfunction is common, frequently identified only through deformation imaging, and early (day 1) RV dysfunction may be associated with clinical outcome.

Disease Severity of Respiratory Syncytial Virus Compared with COVID-19 and Influenza Among Hospitalized Adults Aged ≥60 Years - IVY Network, 20 U.S. States, February 2022-May 2023.

On June 21, 2023, CDC's Advisory Committee on Immunization Practices recommended respiratory syncytial virus (RSV) vaccination for adults aged ≥60 years, offered to individual adults using shared clinical decision-making. Informed use of these vaccines requires an understanding of RSV disease severity. To characterize RSV-associated severity, 5,784 adults aged ≥60 years hospitalized with acute respiratory illness and laboratory-confirmed RSV, SARS-CoV-2, or influenza infection were prospectively enrolled from 25 hospitals in 20 U.S. states during February 1, 2022-May 31, 2023. Multivariable logistic regression was used to compare RSV disease severity with COVID-19 and influenza severity on the basis of the following outcomes: 1) standard flow (<30 L/minute) oxygen therapy, 2) high-flow nasal cannula (HFNC) or noninvasive ventilation (NIV), 3) intensive care unit (ICU) admission, and 4) invasive mechanical ventilation (IMV) or death. Overall, 304 (5.3%) enrolled adults were hospitalized with RSV, 4,734 (81.8%) with COVID-19 and 746 (12.9%) with influenza. Patients hospitalized with RSV were more likely to receive standard flow oxygen, HFNC or NIV, and ICU admission than were those hospitalized with COVID-19 or influenza. Patients hospitalized with RSV were more likely to receive IMV or die compared with patients hospitalized with influenza (adjusted odds ratio = 2.08; 95% CI = 1.33-3.26). Among hospitalized older adults, RSV was less common, but was associated with more severe disease than COVID-19 or influenza. High disease severity in older adults hospitalized with RSV is important to consider in shared clinical decision-making regarding RSV vaccination.

Research Bronchoscopies in Critically Ill Research Participants: An Official American Thoracic Society Workshop Report.

Bronchoscopy for research purposes is a valuable tool to understand lung-specific biology in human participants. Despite published reports and active research protocols using this procedure in critically ill patients, no recent document encapsulates the important safety considerations and downstream applications of this procedure in this setting. The objectives were to identify safe practices for patient selection and protection of hospital staff, provide recommendations for sample procurement to standardize studies, and give guidance on sample preparation for novel research technologies. Seventeen international experts in the management of critically ill patients, bronchoscopy in clinical and research settings, and experience in patient-oriented clinical or translational research convened for a workshop. Review of relevant literature, expert presentations, and discussion generated the findings presented herein. The committee concludes that research bronchoscopy with bronchoalveolar lavage in critically ill patients on mechanical ventilation is valuable and safe in appropriately selected patients. This report includes recommendations on standardization of this procedure and prioritizes the reporting of sample management to produce more reproducible results between laboratories. This document serves as a resource to the community of researchers who endeavor to include bronchoscopy as part of their research protocols and highlights key considerations for the inclusion and safety of research participants.

Responsiveness of Critically Ill Adults With Multimorbidity to Rehabilitation Interventions: A Patient-Level Meta-Analysis Using Individual Pooled Data From Four Randomized Trials.

OBJECTIVE: To explore if patient characteristics (pre-existing comorbidity, age, sex, and illness severity) modify the effect of physical rehabilitation (intervention vs control) for the coprimary outcomes health-related quality of life (HRQoL) and objective physical performance using pooled individual patient data from randomized controlled trials (RCTs). DATA SOURCES: Data of individual patients from four critical care physical rehabilitation RCTs. STUDY SELECTION: Eligible trials were identified from a published systematic review. DATA EXTRACTION: Data sharing agreements were executed permitting transfer of anonymized data of individual patients from four trials to form one large, combined dataset. The pooled trial data were analyzed with linear mixed models fitted with fixed effects for treatment group, time, and trial. DATA SYNTHESIS: Four trials contributed data resulting in a combined total of 810 patients (intervention n = 403, control n = 407). After receiving trial rehabilitation interventions, patients with two or more comorbidities had HRQoL scores that were significantly higher and exceeded the minimal important difference at 3 and 6 months compared with the similarly comorbid control group (based on the Physical Component Summary score (Wald test p = 0.041). Patients with one or no comorbidities who received intervention had no HRQoL outcome differences at 3 and 6 months when compared with similarly comorbid control patients. No patient characteristic modified the physical performance outcome in patients who received physical rehabilitation. CONCLUSIONS: The identification of a target group with two or more comorbidities who derived benefits from the trial interventions is an important finding and provides direction for future investigations into the effect of rehabilitation. The multimorbid post-ICU population may be a select population for future prospective investigations into the effect of physical rehabilitation.

Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Effectiveness of Monovalent mRNA COVID-19 Vaccination in Preventing COVID-19-Associated Invasive Mechanical Ventilation and Death Among Immunocompetent Adults During the Omicron Variant Period - IVY Network, 19 U.S. States, February 1, 2022-January 31, 2023.

As of April 2023, the COVID-19 pandemic has resulted in 1.1 million deaths in the United States, with approximately 75% of deaths occurring among adults aged ≥65 years (1). Data on the durability of protection provided by monovalent mRNA COVID-19 vaccination against critical outcomes of COVID-19 are limited beyond the Omicron BA.1 lineage period (December 26, 2021-March 26, 2022). In this case-control analysis, the effectiveness of 2-4 monovalent mRNA COVID-19 vaccine doses was evaluated against COVID-19-associated invasive mechanical ventilation (IMV) and in-hospital death among immunocompetent adults aged ≥18 years during February 1, 2022-January 31, 2023. Vaccine effectiveness (VE) against IMV and in-hospital death was 62% among adults aged ≥18 years and 69% among those aged ≥65 years. When stratified by time since last dose, VE was 76% at 7-179 days, 54% at 180-364 days, and 56% at ≥365 days. Monovalent mRNA COVID-19 vaccination provided substantial, durable protection against IMV and in-hospital death among adults during the Omicron variant period. All adults should remain up to date with recommended COVID-19 vaccination to prevent critical COVID-19-associated outcomes.

A Pragmatic Pilot Trial Comparing Patient-Triggered Adaptive Pressure Control to Patient-Triggered Volume Control Ventilation in Critically Ill Adults.

BACKGROUND: Patient-triggered adaptive pressure control (APC) continuous mandatory ventilation (CMV) (APC-CMV) has been widely adopted as an alternative ventilator mode to patient-triggered volume control (VC) CMV (VC-CMV). However, the comparative effectiveness of the 2 ventilator modes remains uncertain. We sought to explore clinical and implementation factors pertinent to a future definitive randomized controlled trial assessing APC-CMV versus VC-CMV as an initial ventilator mode strategy. The research objectives in our pilot trial tested clinician adherence and explored clinical outcomes. METHODS: In a single-center pragmatic sequential cluster crossover pilot trial, we enrolled all eligible adults with acute respiratory failure requiring mechanical ventilation admitted during a 9-week period to the medical ICU. Two-week time epochs were assigned a priori in which subjects received either APC-CMV or VC-CMV The primary outcome of the trial was feasibility, defined as 80% of subjects receiving the assigned mode within 1 h of initiation of ICU ventilation. The secondary outcome was proportion of the first 24 h on the assigned mode. Finally, we surveyed clinician stakeholders to understand potential facilitators and barriers to conducting a definitive randomized trial. RESULTS: We enrolled 137 subjects who received 152 discreet episodes of mechanical ventilation during time epochs assigned to APC-CMV (n = 61) and VC-CMV (n = 91). One hundred and thirty-one episodes were included in the prespecified primary outcome. One hundred and twenty-six (96%) received the assigned mode within the first hour of ICU admission (60 of 61 subjects assigned APC-CMV and 66 of 70 assigned VC-CMV). VC-CMV subjects spent a lower proportion of first 24 h (84% [95% CI 78-89]) on the assigned mode than APC-CMV recipients (95% [95% CI 91-100]). Mixed-methods analyses identified preconceived perceptions of subject comfort by clinicians and need for real-time education to address this concern. CONCLUSIONS: In this pilot pragmatic, sequential crossover trial, unit-wide allocation to a ventilator mode was feasible and acceptable to clinicians.

A Survey to Assess Primary Care Physician Awareness of Complications Following Critical Illness.

Background: Survivors of critical illness are at risk for post-intensive care syndrome (PICS, comprised of physical dysfunction, cognitive impairment, and neuropsychiatric disorders including anxiety, depression, and post-traumatic stress). Their family members and caregivers are at risk for PICS-F (PICS-family, comprised of anxiety, depression, post-traumatic stress). PICS and PICS-F are increasingly recognized in critical care; however, the awareness among primary providers of the domains and the terms of PICS/PICS-F is unknown. Objectives: To determine current practice patterns and knowledge among primary care physicians in regards to patients recovering from critical illness; to determine barriers to care of post-critically ill patients. Methods: A paper and electronic survey were developed and randomly distributed to a subset of North Carolina primary care physicians. Survey questions consisted of the following domains: demographics, current practice, barriers to providing care, knowledge of common issues/complications following critical illness, and interest in changing care for survivors of critical illness. Results: One hundred and ninety-six surveys were delivered and 77 completed surveys (39% response rate) were analyzed. Respondents confirmed significant barriers to care of post-critically ill patients including lack of awareness of PICS/PICS-F terminology, insufficient time to spend with patients, and inadequate education of patients/families about recovery after critical illness. Fifty-seven percent of respondents thought a specialized transitional post-ICU clinic would be helpful. Sixty-two percent reported feeling comfortable caring for patients after a critical illness and 75% felt they were aware of common problems encountered after critical illness. However, 84% also thought more education about PICS/PICS-F would be helpful as would a list of common problems seen after critical illness (91%). Conclusions: Significant gaps and barriers to providing optimal post-ICU care by PCPs exist. Providers identified time constraints and educational gaps as domains needing attention. Dedicated post-ICU clinics might provide a bridge to transition care post-critical illness back to primary care providers.

Driving Pressure, Elastance, and Outcomes in a Real-World Setting: A Bi-Center Analysis of Electronic Health Record Data.

Emerging evidence suggests the potential importance of inspiratory driving pressure (DP) and respiratory system elastance (ERS) on outcomes among patients with the acute respiratory distress syndrome. Their association with outcomes among heterogeneous populations outside of a controlled clinical trial is underexplored. We used electronic health record (EHR) data to characterize the associations of DP and ERS with clinical outcomes in a real-world heterogenous population. DESIGN: Observational cohort study. SETTING: Fourteen ICUs in two quaternary academic medical centers. PATIENTS: Adult patients who received mechanical ventilation for more than 48 hours and less than 30 days. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: EHR data from 4,233 ventilated patients from 2016 to 2018 were extracted, harmonized, and merged. A minority of the analytic cohort (37%) experienced a Pao2/Fio2 of less than 300. A time-weighted mean exposure was calculated for ventilatory variables including tidal volume (VT), plateau pressures (PPLAT), DP, and ERS. Lung-protective ventilation adherence was high (94% with VT < 8.5 mL/kg, time-weighted mean VT = 6. 8 mL/kg, 88% with PPLAT ≤ 30 cm H2O). Although time-weighted mean DP (12.2 cm H2O) and ERS (1.9 cm H2O/[mL/kg]) were modest, 29% and 39% of the cohort experienced a DP greater than 15 cm H2O or an ERS greater than 2 cm H2O/(mL/kg), respectively. Regression modeling with adjustment for relevant covariates determined that exposure to time-weighted mean DP (> 15 cm H2O) was associated with increased adjusted risk of mortality and reduced adjusted ventilator-free days independent of adherence to lung-protective ventilation. Similarly, exposure to time-weighted mean ERS greater than 2 cm H2O/(mL/kg) was associated with increased adjusted risk of mortality. CONCLUSIONS: Elevated DP and ERS are associated with increased risk of mortality among ventilated patients independent of severity of illness or oxygenation impairment. EHR data can enable assessment of time-weighted ventilator variables and their association with clinical outcomes in a multicenter real-world setting.

Absolute and Relative Vaccine Effectiveness of Primary and Booster Series of COVID-19 Vaccines (mRNA and Adenovirus Vector) Against COVID-19 Hospitalizations in the United States, December 2021-April 2022.

Background: Coronavirus disease 2019 (COVID-19) vaccine effectiveness (VE) studies are increasingly reporting relative VE (rVE) comparing a primary series plus booster doses with a primary series only. Interpretation of rVE differs from traditional studies measuring absolute VE (aVE) of a vaccine regimen against an unvaccinated referent group. We estimated aVE and rVE against COVID-19 hospitalization in primary-series plus first-booster recipients of COVID-19 vaccines. Methods: Booster-eligible immunocompetent adults hospitalized at 21 medical centers in the United States during December 25, 2021-April 4, 2022 were included. In a test-negative design, logistic regression with case status as the outcome and completion of primary vaccine series or primary series plus 1 booster dose as the predictors, adjusted for potential confounders, were used to estimate aVE and rVE. Results: A total of 2060 patients were analyzed, including 1104 COVID-19 cases and 956 controls. Relative VE against COVID-19 hospitalization in boosted mRNA vaccine recipients versus primary series only was 66% (95% confidence interval [CI], 55%-74%); aVE was 81% (95% CI, 75%-86%) for boosted versus 46% (95% CI, 30%-58%) for primary. For boosted Janssen vaccine recipients versus primary series, rVE was 49% (95% CI, -9% to 76%); aVE was 62% (95% CI, 33%-79%) for boosted versus 36% (95% CI, -4% to 60%) for primary. Conclusions: Vaccine booster doses increased protection against COVID-19 hospitalization compared with a primary series. Comparing rVE measures across studies can lead to flawed interpretations of the added value of a new vaccination regimen, whereas difference in aVE, when available, may be a more useful metric.

Protection of Messenger RNA Vaccines Against Hospitalized Coronavirus Disease 2019 in Adults Over the First Year Following Authorization in the United States.

BACKGROUND: Coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccines were authorized in the United States in December 2020. Although vaccine effectiveness (VE) against mild infection declines markedly after several months, limited understanding exists on the long-term durability of protection against COVID-19-associated hospitalization. METHODS: Case-control analysis of adults (≥18 years) hospitalized at 21 hospitals in 18 states 11 March-15 December 2021, including COVID-19 case patients and reverse transcriptase-polymerase chain reaction-negative controls. We included adults who were unvaccinated or vaccinated with 2 doses of a mRNA vaccine before the date of illness onset. VE over time was assessed using logistic regression comparing odds of vaccination in cases versus controls, adjusting for confounders. Models included dichotomous time (<180 vs ≥180 days since dose 2) and continuous time modeled using restricted cubic splines. RESULTS: A total of 10 078 patients were included, 4906 cases (23% vaccinated) and 5172 controls (62% vaccinated). Median age was 60 years (interquartile range, 46-70), 56% were non-Hispanic White, and 81% had ≥1 medical condition. Among immunocompetent adults, VE <180 days was 90% (95% confidence interval [CI], 88-91) versus 82% (95% CI, 79-85) at ≥180 days (P < .001). VE declined for Pfizer-BioNTech (88% to 79%, P < .001) and Moderna (93% to 87%, P < .001) products, for younger adults (18-64 years) (91% to 87%, P = .005), and for adults ≥65 years of age (87% to 78%, P < .001). In models using restricted cubic splines, similar changes were observed. CONCLUSIONS: In a period largely predating Omicron variant circulation, effectiveness of 2 mRNA doses against COVID-19-associated hospitalization was largely sustained through 9 months.

Elevated Driving Pressure and Elastance Does Not Increase In-Hospital Mortality Among Obese and Severely Obese Patients With Ventilator Dependent Respiratory Failure.

Existing recommendations for mechanical ventilation are based on studies that under-sampled or excluded obese and severely obese individuals. Objective: To determine if driving pressure (DP) and total respiratory system elastance (Ers) differ among normal/overweight (body mass index [BMI] < 30 kg/m2), obese, and severely obese ventilator-dependent respiratory failure (VDRF) patients and if there any associations with clinical outcomes. Design Setting and Participants: Retrospective observational cohort study during 2016-2018 at two tertiary care academic medical centers using electronic health record data from the first 2 full days of mechanical ventilation. The cohort was stratified by BMI classes to measure median DP, time-weighted mean tidal volume, plateau pressure, and Ers for each BMI class. Setting and Participants: Mechanically ventilated patients in medical and surgical ICUs. Main Outcomes and Measures: Primary outcome and effect measures included relative risk of in-hospital mortality, ventilator-free days, ICU length of stay, and hospital length of stay with multivariable adjustment. Results: The cohort included 3,204 patients with 976 (30.4%) and 382 (11.9%) obese and severely obese patients, respectively. Severe obesity was associated with a DP greater than or equal to 15 cm H2O (relative risk [RR], 1.51 [95% CI, 1.26-1.82]) and Ers greater than or equal to 2 cm H2O/(mL/kg) (RR, 1.31 [95% CI, 1.14-1.49]). Despite elevated DP and Ers, there were no differences in in-hospital mortality, ventilator-free days, or ICU length of stay among all three groups. Conclusions and Relevance: Despite higher DP and ERS among obese and severely obese VDRF patients, there were no differences in in-hospital mortality or duration of mechanical ventilation, suggesting that DP has less prognostic value in obese and severely obese VDRF patients.

Early Estimates of Bivalent mRNA Vaccine Effectiveness in Preventing COVID-19-Associated Hospitalization Among Immunocompetent Adults Aged ≥65 Years - IVY Network, 18 States, September 8-November 30, 2022.

Monovalent COVID-19 mRNA vaccines, designed against the ancestral strain of SARS-CoV-2, successfully reduced COVID-19-related morbidity and mortality in the United States and globally (1,2). However, vaccine effectiveness (VE) against COVID-19-associated hospitalization has declined over time, likely related to a combination of factors, including waning immunity and, with the emergence of the Omicron variant and its sublineages, immune evasion (3). To address these factors, on September 1, 2022, the Advisory Committee on Immunization Practices recommended a bivalent COVID-19 mRNA booster (bivalent booster) dose, developed against the spike protein from ancestral SARS-CoV-2 and Omicron BA.4/BA.5 sublineages, for persons who had completed at least a primary COVID-19 vaccination series (with or without monovalent booster doses) ≥2 months earlier (4). Data on the effectiveness of a bivalent booster dose against COVID-19 hospitalization in the United States are lacking, including among older adults, who are at highest risk for severe COVID-19-associated illness. During September 8-November 30, 2022, the Investigating Respiratory Viruses in the Acutely Ill (IVY) Network§ assessed effectiveness of a bivalent booster dose received after ≥2 doses of monovalent mRNA vaccine against COVID-19-associated hospitalization among immunocompetent adults aged ≥65 years. When compared with unvaccinated persons, VE of a bivalent booster dose received ≥7 days before illness onset (median = 29 days) against COVID-19-associated hospitalization was 84%. Compared with persons who received ≥2 monovalent-only mRNA vaccine doses, relative VE of a bivalent booster dose was 73%. These early findings show that a bivalent booster dose provided strong protection against COVID-19-associated hospitalization in older adults and additional protection among persons with previous monovalent-only mRNA vaccination. All eligible persons, especially adults aged ≥65 years, should receive a bivalent booster dose to maximize protection against COVID-19 hospitalization this winter season. Additional strategies to prevent respiratory illness, such as masking in indoor public spaces, should also be considered, especially in areas where COVID-19 community levels are high (4,5).

Effectiveness of Monovalent mRNA Vaccines Against COVID-19-Associated Hospitalization Among Immunocompetent Adults During BA.1/BA.2 and BA.4/BA.5 Predominant Periods of SARS-CoV-2 Omicron Variant in the United States - IVY Network, 18 States, December 26, 2021-August 31, 2022.

The SARS-CoV-2 Omicron variant (B.1.1.529 or BA.1) became predominant in the United States by late December 2021 (1). BA.1 has since been replaced by emerging lineages BA.2 (including BA.2.12.1) in March 2022, followed by BA.4 and BA.5, which have accounted for a majority of SARS-CoV-2 infections since late June 2022 (1). Data on the effectiveness of monovalent mRNA COVID-19 vaccines against BA.4/BA.5-associated hospitalizations are limited, and their interpretation is complicated by waning of vaccine-induced immunity (2-5). Further, infections with earlier Omicron lineages, including BA.1 and BA.2, reduce vaccine effectiveness (VE) estimates because certain persons in the referent unvaccinated group have protection from infection-induced immunity. The IVY Network† assessed effectiveness of 2, 3, and 4 doses of monovalent mRNA vaccines compared with no vaccination against COVID-19-associated hospitalization among immunocompetent adults aged ≥18 years during December 26, 2021-August 31, 2022. During the BA.1/BA.2 period, VE 14-150 days after a second dose was 63% and decreased to 34% after 150 days. Similarly, VE 7-120 days after a third dose was 79% and decreased to 41% after 120 days. VE 7-120 days after a fourth dose was 61%. During the BA.4/BA.5 period, similar trends were observed, although CIs for VE estimates between categories of time since the last dose overlapped. VE 14-150 days and >150 days after a second dose was 83% and 37%, respectively. VE 7-120 days and >120 days after a third dose was 60%and 29%, respectively. VE 7-120 days after the fourth dose was 61%. Protection against COVID-19-associated hospitalization waned even after a third dose. The newly authorized bivalent COVID-19 vaccines include mRNA from the ancestral SARS-CoV-2 strain and from shared mRNA components between BA.4 and BA.5 lineages and are expected to be more immunogenic against BA.4/BA.5 than monovalent mRNA COVID-19 vaccines (6-8). All eligible adults aged ≥18 years§ should receive a booster dose, which currently consists of a bivalent mRNA vaccine, to maximize protection against BA.4/BA.5 and prevent COVID-19-associated hospitalization.

Vaccine effectiveness of primary series and booster doses against covid-19 associated hospital admissions in the United States: living test negative design study.

OBJECTIVE: To compare the effectiveness of a primary covid-19 vaccine series plus booster doses with a primary series alone for the prevention of hospital admission with omicron related covid-19 in the United States. DESIGN: Multicenter observational case-control study with a test negative design. SETTING: Hospitals in 18 US states. PARTICIPANTS: 4760 adults admitted to one of 21 hospitals with acute respiratory symptoms between 26 December 2021 and 30 June 2022, a period when the omicron variant was dominant. Participants included 2385 (50.1%) patients with laboratory confirmed covid-19 (cases) and 2375 (49.9%) patients who tested negative for SARS-CoV-2 (controls). MAIN OUTCOME MEASURES: The main outcome was vaccine effectiveness against hospital admission with covid-19 for a primary series plus booster doses and a primary series alone by comparing the odds of being vaccinated with each of these regimens versus being unvaccinated among cases versus controls. Vaccine effectiveness analyses were stratified by immunosuppression status (immunocompetent, immunocompromised). The primary analysis evaluated all covid-19 vaccine types combined, and secondary analyses evaluated specific vaccine products. RESULTS: Overall, median age of participants was 64 years (interquartile range 52-75 years), 994 (20.8%) were immunocompromised, 85 (1.8%) were vaccinated with a primary series plus two boosters, 1367 (28.7%) with a primary series plus one booster, and 1875 (39.3%) with a primary series alone, and 1433 (30.1%) were unvaccinated. Among immunocompetent participants, vaccine effectiveness for prevention of hospital admission with omicron related covid-19 for a primary series plus two boosters was 63% (95% confidence interval 37% to 78%), a primary series plus one booster was 65% (58% to 71%), and for a primary series alone was 37% (25% to 47%) (P<0.001 for the pooled boosted regimens compared with a primary series alone). Vaccine effectiveness was higher for a boosted regimen than for a primary series alone for both mRNA vaccines (BNT162b2 (Pfizer-BioNTech): 73% (44% to 87%) for primary series plus two boosters, 64% (55% to 72%) for primary series plus one booster, and 36% (21% to 48%) for primary series alone (P<0.001); mRNA-1273 (Moderna): 68% (17% to 88%) for primary series plus two boosters, 65% (55% to 73%) for primary series plus one booster, and 41% (25% to 54%) for primary series alone (P=0.001)). Among immunocompromised patients, vaccine effectiveness for a primary series plus one booster was 69% (31% to 86%) and for a primary series alone was 49% (30% to 63%) (P=0.04). CONCLUSION: During the first six months of 2022 in the US, booster doses of a covid-19 vaccine provided additional benefit beyond a primary vaccine series alone for preventing hospital admissions with omicron related covid-19. READERS' NOTE: This article is a living test negative design study that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication.