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The goal of hemodynamic resuscitation is to optimize the microcirculation of organs to meet their oxygen and metabolic needs. Clinicians are currently blind to what is happening in the microcirculation of organs, which prevents them from achieving an additional degree of individualization of the hemodynamic resuscitation at tissue level. Indeed, clinicians never know whether optimization of the microcirculation and tissue oxygenation is actually achieved after macrovascular hemodynamic optimization. The challenge for the future is to have noninvasive, easy-to-use equipment that allows reliable assessment and immediate quantitative analysis of the microcirculation at the bedside. There are different methods for assessing the microcirculation at the bedside; all have strengths and challenges. The use of automated analysis and the future possibility of introducing artificial intelligence into analysis software could eliminate observer bias and provide guidance on microvascular-targeted treatment options. In addition, to gain caregiver confidence and support for the need to monitor the microcirculation, it is necessary to demonstrate that incorporating microcirculation analysis into the reasoning guiding hemodynamic resuscitation prevents organ dysfunction and improves the outcome of critically ill patients.

This article provides a comprehensive overview of past studies of aircraft icing. Special attention is paid to the following aspects. First, the causes, types, severity and natural parameters of aircraft icing are introduced. Then the various effects of icing on the aerodynamic characteristics of the aircraft, stability, controllability, as well as existing evaluation methods are generalized and analyzed. The following is a simple introduction to the recent problem of icing with supercooled large droplets, and whose nature is carefully described in the article (SLD). Finally, a series of aviation accidents that have occurred in recent years due to icing is analyzed. Previous lessons should be adopted and disseminated by subsequent generations in order to avoid accidents due to icing of aircraft. Based on the consideration of such a wide range of issues related to icing, ways to prevent it using various methods and devices are considered, and the effectiveness of such methods to prevent icing of specific aircraft units is compared.

OBJECTIVES: The goal of this study is to identify clinical variables associated with bacteremia. Such data could provide a rational basis for blood culture testing in emergency department (ED) patients with suspected infection. METHODS: This is a secondary analysis of a prospective cohort of ED patients with suspected infection. Data collected included demographics, vital signs, medical history, suspected source of infection, laboratory and blood culture results and outcomes. Bacteremia was defined as a positive blood culture by Centers for Disease Control criteria. Clinical variables associated with bacteremia on univariate logistic regression were entered into a multivariable model. RESULTS: There were 5630 patients enrolled with an average age of 59.9 ± 19.9 years, and 54% were female. Blood cultures were obtained on 3310 (58.8%). There were 409 (12.4%) positive blood cultures, of which 68 (16.6%) were methicillin-resistant Staphylococcus aureus (MRSA) and 161 (39.4%) were Gram negatives. Ten covariates (respiratory failure, vasopressor use, neutrophilia, bandemia, thrombocytopenia, indwelling venous catheter, abnormal temperature, suspected line or urinary infection, or endocarditis) were associated with all-cause bacteremia in the final model (c-statistic area under the curve [AUC], 0.71). Additional factors associated with MRSA bacteremia included end-stage renal disease (odds ratio [OR], 3.9; 95% confidence interval [CI], 1.9-7.8) and diabetes (OR, 2.0; 95% CI, 1.1-3.6) (AUC, 0.73). Factors strongly associated with Gram-negative bacteremia included vasopressor use in the ED (OR, 2.8; 95% CI, 1.7-4.6), bandemia (OR, 3.5; 95% CI, 2.3-5.3), and suspected urinary infection (OR, 4.0; 95% CI, 2.8-5.8) (AUC, 0.75). CONCLUSIONS: This study identified several clinical factors associated with bacteremia as well as MRSA and Gram-negative subtypes, but the magnitude of their associations is limited. Combining these covariates into a multivariable model moderately increases their predictive value. [ABSTRACT FROM AUTHOR]

OBJECTIVE: : Regionalization of care is a potential strategy for the management of shock. There are no data describing the regional distribution of patients with out-of-hospital shock. We sought to describe the incidence, demographic, clinical, and regional characteristics of patients with traumatic and nontraumatic medical shock treated by out-of-hospital emergency medical services. DESIGN: : Descriptive study using Pennsylvania statewide emergency medical services patient care data. SETTING: : Commonwealth of Pennsylvania, 2006-2008. PATIENTS: : Adult (age >=18 yrs) noncardiac arrest patients with shock, defined as initial systolic blood pressure <=80 mm Hg. INTERVENTIONS: : None. MEASUREMENTS AND MAIN RESULTS: : We compared patient characteristics, demographics, emergency medical services treatment, and regional differences between traumatic and nontraumatic medical shock. Of 3,327,306 adult nonarrest patients, 42,941 (1.29%; 95% confidence interval, 1.28% to 1.30%) had shock in the field, including 39,424 with medical shock and 3,517 with traumatic shock. Patients with medical shock were more likely to be older, female, and treated by rural emergency medical services agencies and experienced longer transport times. County-level annual shock rates varied for medical (median, 99; interquartile range, 44-273; range, 5-1634) and traumatic (median, seven; interquartile range, 3-18; range, 0-300) cases. Per-capita shock rates varied for medical (median, 105 per 100,000 population; interquartile range, 83-128; range, 37-263) and traumatic (median, seven per 100,000 population; interquartile range, 5-10; range, 0-39) cases. The correlation between county-level total annual medical and traumatic shock rates was strong ([rho] = .80). CONCLUSIONS: : While sharing similar regional distributions, key differences exist between emergency medical services patients with traumatic and nontraumatic shock. These differences identify opportunities for and barriers to regionalizing emergency medical services care of patients with shock. [ABSTRACT FROM AUTHOR]

Study Objective: We assess the diagnostic accuracy of plasma neutrophil gelatinase-associated lipocalin (NGAL) to predict acute kidney injury in emergency department (ED) patients with suspected sepsis. Methods: We conducted a secondary analysis of a prospective observational study of a convenience sample of patients from 10 academic medical center EDs. Inclusion criteria were adult patients aged 18 years or older, with suspected infection or a serum lactate level greater than 2.5 mmol/L; 2 or more systemic inflammatory response syndrome criteria; and a subsequent serum creatinine level obtained within 12 to 72 hours of enrollment. Exclusion criteria were pregnancy, do-not-resuscitate status, cardiac arrest, or dialysis dependency. NGAL was measured in plasma collected at ED presentation. Acute kidney injury was defined as an increase in serum creatinine measurement of greater than 0.5 mg/dL during 72 hours. Results: There were 661 patient enrolled, with 24 cases (3.6%) of acute kidney injury that developed within 72 hours after ED presentation. Median plasma NGAL levels were 134 ng/mL (interquartile range 57 to 277 ng/mL) in patients without acute kidney injury and 456 ng/mL (interquartile range 296 to 727 ng/mL) in patients with acute kidney injury. Plasma NGAL concentrations of greater than 150 ng/mL were 96% sensitive (95% confidence interval [CI] 79% to 100%) and 51% (95% CI 47% to 55%) specific for acute kidney injury. In comparison, to achieve equivalent sensitivity with initial serum creatinine level at ED presentation required a cutoff of 0.7 mg/dL and resulted in specificity of 17% (95% CI 14% to 20%). Conclusion: In this preliminary investigation, increased plasma NGAL concentrations measured on presentation to the ED in patients with suspected sepsis were associated with the development of acute kidney injury. Our findings support NGAL as a promising new biomarker for acute kidney injury; however, further research is warranted. [ABSTRACT FROM AUTHOR]

Context: Goal-directed resuscitation for severe sepsis and septic shock has been reported to reduce mortality when applied in the emergency department.Objective: To test the hypothesis of noninferiority between lactate clearance and central venous oxygen saturation (ScvO2) as goals of early sepsis resuscitation.Design, Setting, and Patients: Multicenter randomized, noninferiority trial involving patients with severe sepsis and evidence of hypoperfusion or septic shock who were admitted to the emergency department from January 2007 to January 2009 at 1 of 3 participating US urban hospitals.Interventions: We randomly assigned patients to 1 of 2 resuscitation protocols. The ScvO2 group was resuscitated to normalize central venous pressure, mean arterial pressure, and ScvO2 of at least 70%; and the lactate clearance group was resuscitated to normalize central venous pressure, mean arterial pressure, and lactate clearance of at least 10%. The study protocol was continued until all goals were achieved or for up to 6 hours. Clinicians who subsequently assumed the care of the patients were blinded to the treatment assignment.Main Outcome Measure: The primary outcome was absolute in-hospital mortality rate; the noninferiority threshold was set at Delta equal to -10%.Results: Of the 300 patients enrolled, 150 were assigned to each group and patients were well matched by demographic, comorbidities, and physiological features. There were no differences in treatments administered during the initial 72 hours of hospitalization. Thirty-four patients (23%) in the ScvO2 group died while in the hospital (95% confidence interval [CI], 17%-30%) compared with 25 (17%; 95% CI, 11%-24%) in the lactate clearance group. This observed difference between mortality rates did not reach the predefined -10% threshold (intent-to-treat analysis: 95% CI for the 6% difference, -3% to 15%). There were no differences in treatment-related adverse events between the groups.Conclusion: Among patients with septic shock who were treated to normalize central venous and mean arterial pressure, additional management to normalize lactate clearance compared with management to normalize ScvO2 did not result in significantly different in-hospital mortality.Trial Registration: clinicaltrials.gov Identifier: NCT00372502. [ABSTRACT FROM AUTHOR]

Study Objective: Abnormal (both low and high) central venous saturation (ScvO(2)) is associated with increased mortality in emergency department (ED) patients with suspected sepsis.Methods: This was a secondary analysis of 4 prospectively collected registries of ED patients treated with early goal-directed therapy-based sepsis resuscitation protocols from 4 urban tertiary care hospitals. Inclusion criteria were sepsis, hypoperfusion defined by systolic blood pressure less than 90 mm Hg or lactate level greater than or equal to 4 mmol/L, and early goal-directed therapy treatment. ScvO(2) levels were stratified into 3 groups: hypoxia (ScvO(2) <70%); normoxia (ScvO(2) 71% to 89%); and hyperoxia (ScvO(2) 90% to 100%). The primary exposures were initial ScvO(2) and maximum ScvO(2) achieved, with the primary outcome as inhospital mortality. Multivariate analysis was performed.Results: There were 619 patients who met criteria and were included. For the maximum ScvO(2), compared with the mortality rate in the normoxia group of 96 of 465 (21%; 95% confidence interval [CI] 17% to 25%), both the hypoxia mortality rate, 25 of 62 (40%; 95% CI 29% to 53%) and hyperoxia mortality rate, 31 of 92 (34%; 95% CI 25% to 44%) were significantly higher, which remained significant in a multivariate modeling. When the initial ScvO(2) measurement was analyzed in a multivariate model, only hyperoxia was significantly higher.Conclusion: The maximum ScvO(2) value achieved in the ED (both abnormally low and high) was associated with increased mortality. In multivariate analysis for initial ScvO(2), the hyperoxia group was associated with increased mortality, but not the hypoxia group. This study suggests that future research aimed at targeting methods to normalize high ScvO(2) values by therapies that improve microcirculatory flow or mitochondrial dysfunction may be warranted. [ABSTRACT FROM AUTHOR]

Objective: The emergency department (ED) often serves as the first site for the recognition and treatment of patients with suspected severe sepsis. However, few evaluations of the national epidemiology and distribution of severe sepsis in the ED exist. We sought to determine national estimates of the number, timing, ED length of stay, and case distribution of patients presenting to the ED with suspected severe sepsis.Design: Analysis of 2001-2004 ED data from the National Hospital Ambulatory Medical Care Survey.Setting: National multistage probability sample of United States ED data.Patients: Adult (age, >or=18 yrs) patients with suspected severe sepsis, defined as the concurrent presence of an infec-tion (ED International Classification of Diseases, 9th Revision; ICD-9) diagnosis of infection, or a triage temperature <96.8 degrees F or >or=100.4 degrees F) and organ dysfunction (ED ICD-9) diagnosis of organ dysfunction, intubation, or a triage systolic blood pressure Interventions: None.Measurements: Estimated number of ED patients presenting with suspected severe sepsis, and their times of arrival, ED lengths of stay, and clinical characteristics.Main Results: Of 331.5 million adult ED visits, approximately 2.3 million (571,000 annually, 0.69%; 95% confidence interval [CI], 0.61-0.77%) were for suspected severe sepsis. Mean ED length of stay for suspected severe sepsis was 4.7 hrs (95% CI, 4.3-5.1 hrs), with 20.4% spending >6 hrs in the ED. Of suspected severe sepsis patients, 20.6% presented to a low-volume ED (Conclusions: Suspected severe sepsis patients account for more than 500,000 ED visits annually, with individual patients spending an average of almost 5 hrs in the ED. These national data offer key systemwide information for designing and implementing strategies for severe sepsis treatment. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the predictive performance for 1-yr mortality of the previously derived and validated Mortality in Emergency Department Sepsis (MEDS) score. DESIGN: Prospective cohort study. PATIENTS: Consecutive adult (aged > or =18 yrs) emergency department patients presenting to an urban, tertiary care, university hospital were eligible if they had a clinically suspected infection as indicated by the decision to obtain a blood culture. The enrollment period was between February 1, 2000, and February 1, 2001. Of 3,926 eligible patient visits, 3,762 (96%) were enrolled and 3,102 unique first visits were analyzed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 667 patients (21.5%) died within 1 yr. The unadjusted 1-yr mortality rates for the MEDS risk groups were: very low risk, 7%; low risk, 20%; moderate risk, 37%; high risk, 64%; very high risk, 80%. Using a Cox proportional hazard model that controlled for age, sex, and Charlson co-morbidity index, the 1-yr hazard ratios compared with the baseline very low-risk group were: low risk, 2.2 (1.7-2.9); moderate risk, 3.5 (2.7-4.6); high risk, 6.7 (4.9-9.3); and very high risk, 10.5 (7.2-15.4). The groups were significantly different (p < .0001). CONCLUSIONS: Although the score was initially derived for 28-day in-hospital mortality, our results indicate that the MEDS score also predicts patient survival at 1 yr after index hospital visit with suspected infection. The score needs external validation before widespread use. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: Epidemiologic data on emergency department (ED) patients with sepsis are limited. Inpatient discharge records from 1979 to 2000 show that hospitalizations for sepsis are increasing. We examine the epidemiology of sepsis in US EDs and the hypothesis that sepsis visits are increasing. METHODS: The National Hospital Ambulatory Medical Care Survey data (1992 to 2001) provided nationally representative estimates of frequency and disposition in adult ED visits for sepsis. Sepsis visits were identified using International Classification of Diseases, Ninth Revision, Clinical Modification codes; severe sepsis was defined as sepsis in conjunction with organ failure. RESULTS: Of 712 million adult visits during the 10-year period, approximately 2.8 million (0.40%, 95% confidence interval [CI] 0.33% to 0.46%) were related to sepsis. We found no significant increase in overall ED visits for sepsis from 1992 to 2001 (P for trend=.09). ED patients with sepsis were more likely to be elderly, non-Hispanic, and publicly insured and to arrive by ambulance compared with nonsepsis patients (all P<.01). The overall admission rate was 87% (95% CI 82% to 92%), with only 12% (95% CI 8% to 16%) of patients admitted to the ICU. The most frequent codiagnoses were pneumonia (13%), urinary tract infection (13%), and dehydration (11%). Severe sepsis accounted for 8% (95% CI 5% to 11%) of sepsis visits, for an annual incidence of 0.01%; 98% of patients with severe sepsis were admitted. CONCLUSION: In contrast to data from hospital discharges, ED visits for sepsis demonstrated no increase. Most ED visits for sepsis resulted in admission to non-critical care units. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To describe the effectiveness of a comprehensive, interdisciplinary sepsis treatment protocol with regard to both implementation and outcomes and to compare the mortality rates and therapies of patients with septic shock with similar historical controls. DESIGN: Prospective, interventional cohort study with a historical control comparison group. SETTING: Urban, tertiary care, university hospital with 46,000 emergency department visits and 4,100 intensive care unit admissions annually. PATIENTS: Inclusion criteria were a) emergency department patients aged > or =18 yrs, b) suspected infection, and c) lactate of >4 mmol/L or septic shock. Exclusion criteria were a) emergent operation, b) prehospital cardiac arrest, and c) comfort measures only. Time period: protocol, November 10, 2003, through November 9, 2004; historical controls, February 1, 2000, through January 31, 2001. INTERVENTION: A sepsis treatment pathway incorporating empirical antibiotics, early goal-directed therapy, drotrecogin alfa, steroids, intensive insulin therapy, and lung-protective ventilation. MEASUREMENTS AND MAIN RESULTS: There were 116 protocol patients, with a mortality rate of 18% (11-25%), of which 79 patients had septic shock. Comparing these patients with 51 historical controls, protocol patients received more fluid (4.0 vs. 2.5 L crystalloid, p < .001), earlier antibiotics (90 vs. 120 mins, p < .013), more appropriate empirical coverage (97% vs. 88%, p < .05), more vasopressors in the first 6 hrs (80% vs. 45%, p < .001), tighter glucose control (mean morning glucose, 123 vs. 140, p < .001), and more frequent assessment of adrenal function (82% vs. 10%, p < .001), with a nonstatistically significant increase in dobutamine use (14% vs. 4%, p = .06) and red blood cell transfusions (30% vs. 18%, p = .07) in the first 24 hrs. For protocol patients with septic shock, 28-day in-hospital mortality was 20.3% compared with 29.4% for historical controls (p = .3). CONCLUSIONS: Clinical implementation of a comprehensive sepsis treatment protocol is feasible and is associated with changes in therapies such as time to antibiotics, intravenous fluid delivery, and vasopressor use in the first 6 hrs. No statistically significant decrease in mortality was demonstrated, as this trial was not sufficiently powered to assess mortality benefits. [ABSTRACT FROM AUTHOR]

STUDY OBJECTIVE: Little is known about risk-stratification biomarkers in emergency department (ED) patients with suspected infection, and lactate is a biologically plausible candidate. We determine whether a serum venous lactate is associated with an increased risk of death in ED patients with infection. METHODS: This was a prospective cohort study in an urban, academic medical center with 50,000 annual ED visits. A total of 1,278 consecutive patient visits met enrollment criteria between July 24, 2003, and March 24, 2004, and all patients were enrolled. Inclusion criteria were age 18 years or older, serum lactate level obtained, and admission to the hospital with an infection-related diagnosis. The main outcome measure was all-cause 28-day inhospital mortality and death within 3 days of presentation. RESULTS: Among 1,278 patient visits, there were 105 (8.2%) deaths during hospitalization, with 55 (4.3%) of 1,278 deaths occurring in the first 3 days. Mortality rates increased as lactate increased: 43 (4.9%) of 877 of patients with a lactate level between 0 and 2.5 mmol/L died, 24 (9.0%) of 267 patients with a lactate level between 2.5 and 4.0 mmol/L died, and 38 (28.4%) of 134 patients with a lactate level greater than or equal to 4.0 mmol/L died. Lactate level greater than or equal to 4.0 mmol/L was 36% (95% confidence interval [CI] 27% to 45%) sensitive and 92% (95% CI 90% to 93%) specific for any death; it was 55% (95% CI 41% to 68%) sensitive and 91% (95% CI 90% to 93%) specific for death within 3 days. CONCLUSION: In this cohort of ED patients with signs and symptoms suggestive of infection, our results support serum venous lactate level as a promising risk-stratification tool. Multicenter validation, as well as comparison of the lactate level with clinical predictors, needs to be done before widespread implementation. [ABSTRACT FROM AUTHOR]

Introduction: Near-infrared spectroscopy (NIRS) noninvasively measures peripheral tissue oxygen saturation (StO₂). NIRS may be utilized along with a vascular occlusion test, in which limb blood flow is temporarily occluded and released, to quantify a tissue bed's rate of oxygen exchange during ischemia and recovery. The objective of this study was to test the hypothesis that NIRS-derived StO₂ measures (StO₂ initial, StO₂ occlusion and StO₂ recovery) identify patients who are in shock and at increased risk of organ dysfunction (Sequential Organ Failure Assessment (SOFA) score ≥ 2 at 24 hours) and dying in the hospital.Methods: This prospective, observational study comprised a convenience sample of three cohorts of adult patients (age > 17 years) at three urban university emergency departments: (1) a septic shock cohort (systolic blood pressure < 90 after fluid challenge; the "SHOCK" cohort, n = 58), (2) a sepsis without shock cohort (the "SEPSIS" cohort, n = 60) and emergency department patients without infection (n = 50). We measured the StO₂ initial, StO₂ occlusion and StO₂ recovery slopes for all patients. Outcomes were sepsis syndrome severity, organ dysfunction (SOFA score at 24 hours) and in-hospital mortality.Results: Among the 168 patients enrolled, mean initial StO₂ was lower in the SHOCK cohort than in the SEPSIS cohort (76% vs 81%), with an impaired occlusion slope (-10.2 and 5.2%/minute vs -13.1 and 4.4%/minute) and an impaired recovery slope (2.4 and 1.6%/second vs 3.9 and 1.7%/second) (P < 0.001 for all). The recovery slope was well-correlated with SOFA score at 24 hours (-0.35; P < 0.001), with a promising area under the curve (AUC) for mortality of 0.81. The occlusion slope correlation with SOFA score at 24 hours was 0.21 (P < 0.02), with a fair mortality AUC of 0.70. The initial StO₂ was significantly but less strongly correlated with SOFA score at 24 hours (-0.18; P < 0.04), with a poor mortality AUC of 0.56.Conclusions: NIRS measurements for the StO₂ initial, StO₂ occlusion and StO₂ recovery slope were abnormal in patients with septic shock compared to sepsis patients. The recovery slope was most strongly associated with organ dysfunction and mortality. Further validation is warranted.Trial Registration: NCT01062685. [ABSTRACT FROM AUTHOR]

Background: In test-negative studies of vaccine effectiveness (VE), including patients with co-circulating, vaccine-preventable, respiratory pathogens in the control group for the pathogen of interest can introduce a downward bias on VE estimates., Methods: A multicenter sentinel surveillance network in the US prospectively enrolled adults hospitalized with acute respiratory illness from September 1, 2022-March 31, 2023. We evaluated bias in estimates of VE against influenza-associated and COVID-19-associated hospitalization based on: inclusion vs exclusion of patients with a co-circulating virus among VE controls; observance of VE against the co-circulating virus (rather than the virus of interest), unadjusted and adjusted for vaccination against the virus of interest; and observance of influenza or COVID-19 against a sham outcome of respiratory syncytial virus (RSV)., Results: Overall VE against influenza-associated hospitalizations was 6 percentage points lower when patients with COVID-19 were included in the control group, and overall VE against COVID-19-associated hospitalizations was 2 percentage points lower when patients with influenza were included in the control group. Analyses of VE against the co-circulating virus and against the sham outcome of RSV showed that downward bias was largely attributable the correlation of vaccination status across pathogens, but also potentially attributable to other sources of residual confounding in VE models., Conclusion: Excluding cases of confounding respiratory pathogens from the control group in VE analysis for a pathogen of interest can reduce downward bias. This real-world analysis demonstrates that such exclusion is a helpful bias mitigation strategy, especially for measuring influenza VE, which included a high proportion of COVID-19 cases among controls., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Michelle Ng Gong reports grants from NHLBI as a HART co-investigator and APS steering committee co-chair, support for travel to the ATS meeting, participating on an advisory board from Novartis, Philips Healthcase, Regeneron, and Radiomater, and participating on the DSMB for Best clinical trials, outside the submitted work. Carlos G. Grijalva reports receiving compensation for participation in an advisory board for Merck, and receiving research support from CDC, NIH, FDA, AHRQ and SyneosHealth, outside the submitted work. Natasha Halasa receives current support from Merck (investigator-initiated grant), past support from Sanofi and Quidel, and served on an advisory board for Seqirus, outside the submitted work. Akram Khan reports receiving research funding from Dompe pharmaceuticals, 4D Medical, Eli Lilly, and Direct Biologics for patient enrollment in studies, outside the submitted work. Adam S. Lauring reports consulting fees and research support from Roche, and research funding from NIAID, NSF, CDC, and Burroughs Wellcome Fund, outside the submitted work. Ithan Peltan reports funding from NIH (R35GM151147), funding from NHLBI and Janssen, and payments to his institution from Regeneron, Bluejay Diagnostics, and Novartis, outside the submitted work. Mayur Ramesh reports participating on an advisory board for AstraZeneca, Moderna, and Pfizer, outside the submitted work. Ivana A Vaughn reports funding from CDC via University of Michigan for US Flu VE Network, funding from eMaxHealth through her institution, and funding from Lilly USA through her institution, outside the submitted work. No other potential conflicts of interest were disclosed., (Published by Elsevier Ltd.)

Background: Assessments of COVID-19 vaccine effectiveness are needed to monitor the protection provided by updated vaccines against severe COVID-19. We evaluated the effectiveness of original monovalent and bivalent (ancestral strain and Omicron BA.4/5) COVID-19 vaccination against COVID-19-associated hospitalization and severe in-hospital outcomes., Methods: During September 8, 2022 to August 31, 2023, adults aged ≥ 18 years hospitalized with COVID-19-like illness were enrolled at 26 hospitals in 20 US states. Using a test-negative case-control design, we estimated vaccine effectiveness (VE) with multivariable logistic regression adjusted for age, sex, race/ethnicity, admission date, and geographic region., Results: Among 7028 patients, 2924 (41.6%) were COVID-19 case patients, and 4104 (58.4%) were control patients. Compared to unvaccinated patients, absolute VE against COVID-19-associated hospitalization was 6% (-7%-17%) for original monovalent doses only (median time since last dose [IQR] = 421 days [304-571]), 52% (39%-61%) for a bivalent dose received 7-89 days earlier, and 13% (-10%-31%) for a bivalent dose received 90-179 days earlier. Absolute VE against COVID-19-associated invasive mechanical ventilation or death was 51% (34%-63%) for original monovalent doses only, 61% (35%-77%) for a bivalent dose received 7-89 days earlier, and 50% (11%-71%) for a bivalent dose received 90-179 days earlier., Conclusion: Bivalent vaccination provided protection against COVID-19-associated hospitalization and severe in-hospital outcomes within 3 months of receipt, followed by a decline in protection to a level similar to that remaining from previous original monovalent vaccination by 3-6 months. These results underscore the benefit of remaining up to date with recommended COVID-19 vaccines., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Because 20-30% of patients with sepsis deteriorate to critical illness, biomarkers that provide accurate early prognosis may identify which patients need more intensive treatment versus safe early discharge. The objective was to test the performance of sVEGFR2, suPAR and PCT, alone or combined with clinical signs and symptoms, for the prediction of clinical deterioration. This prospective observational study enrolled patients with suspected infection who met SIRS criteria without organ dysfunction (delta SOFA <2 from baseline) from 16 emergency departments. The primary endpoint was clinical deterioration (increased SOFA score ≥2 points, new or increased organ support, or death) within 72 hours of enrollment. Diagnosis and classification of infection status were adjudicated. 724 patients were enrolled, (54% men, median age 55 [38-70] y-o). Infection origin was abdominopelvic (21%), skin and soft tissues (17%), urinary (16%) and pulmonary (15%). 176 (24%) patients deteriorated, with a 28-day mortality of 1.4%. They had lower sVEGFR2 level (6.17 [5.00-7.40] vs 6.52 [5.40-7.84], p=0.024), higher circulating suPAR (5.25 [3.86-7.50] vs 4.18 [3.16-5.68], p<0.001) and higher PCT level (0.32 [0.08-1.80] vs 0.18 [0.05-0.98], p=0.004). suPAR demonstrated superior performance (AUC=0.65 [0.60-0.70]), compared to other biomarkers (PCT, AUC=0.57 [0.52-0.62] and sVEGFR2, AUC=0.58 [0.53-0.64]). Maximum accuracy was achieved from the combination of clinical information, sVEGFR2 and suPAR, yielding an AUC of 0.74 [0.69-0.78] and NPV 0.90 [0.88-0.94]. sVEGFR2 and suPAR were insufficiently accurate to rule out clinical deterioration. Panels of biomarkers will likely be needed to capture the heterogeneous mechanistic pathways involved in sepsis-related organ failure., (© 2024. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

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., (Copyright © 2024 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) has enhanced our understanding of host immune mechanisms in small cohorts, particularly in diseases with complex and heterogeneous immune responses such as sepsis. However, PBMC isolation from blood requires technical expertise, training, and approximately two hours of onsite processing using Ficoll density gradient separation ('Ficoll') for scRNA-seq compatibility, precluding large-scale sample collection at most clinical sites. To minimize onsite processing, we developed Cryo-PRO (Cryopreservation with PBMC Recovery Offsite), a method of PBMC isolation from cryopreserved whole blood that allows immediate onsite sample cryopreservation and subsequent PBMC isolation in a central laboratory prior to sequencing. We compared scRNA-seq results from samples processed using Cryo-PRO versus standard onsite Ficoll separation in 23 patients with sepsis. Critical scRNA-seq outputs including cell substate fractions and marker genes were similar for each method across multiple cell types and substates, including an important monocyte substate enriched in patients with sepsis (Pearson correlation 0.78, p<0.001; 70% of top marker genes shared). Cryo-PRO reduced onsite sample processing time from >2 hours to <15 minutes and was reproducible across two enrollment sites, thus demonstrating potential for expanding scRNA-seq in multicenter studies of sepsis and other diseases.

In absence of a "gold standard", a standardized clinical adjudication process was developed for a registrational trial of a transcriptomic host response (HR) test. Two physicians independently reviewed clinical data to adjudicate presence and source of bacterial and viral infections in emergency department patients. Discordant cases were resolved by a third physician. Agreement among 955 cases was 74.1% (708/955) for bacterial, 75.6% (722/955) for viral infections, and 71.2% (680/955) overall. Most discordances were minor (85.2%; 409/480) versus moderate (11.7%; 56/480) or complete (3.3%; 16/480). Concordance levels were lowest for bacterial skin and soft tissue infections (8.2%) and for viral respiratory tract infections (4.5%). This robust adjudication process can be used to evaluate HR tests and other diagnostics by regulatory agencies and for educating clinicians, laboratorians, and clinical researchers. Clinicaltrials.gov NCT04094818. SUMMARY: Without a gold standard for evaluating host response tests, clinical adjudication is a robust reference standard that is essential to determine the true infection status in diagnostic registrational clinical studies., Competing Interests: Declaration of competing interest NNW and OL: The authors are employees and stock option holders of Inflammatix, Inc. CH: The author is a consultant of Inflammatix, Inc. JC: The author has no conflicts of interest to disclose. LM: The author has received honoraria from Inflammatix, Inc. and Thermofisher and was a consultant to Cytovale. She is an advisor for Roche, Biomerieux, and Talis Biomedical. JH: The author has served as a consultant to Beckman Coulter on the use of Artificial Intelligence tools in the practice of emergency medicine. EBH: The author has no conflicts of interest to disclose. EM: The author has no conflicts of interest to disclose. RR: The author has received research funding through his University from Inflammatix, Inc. and has served as a paid scientific expert advisor to Inflammatix, Inc. DS: The author has no conflicts of interest to disclose. RH: The author has no conflicts of interest to disclose. EAM: The author has received research funding from Inflammatix, Inc. WHS: The author has received research funding from Inflammatix, Inc. HAS: The author has no conflicts of interest to disclose. JSS: The author has no conflicts of interest to disclose. HCSK: The author has no conflicts of interest to disclose. AW: The author has served as a consultant to Inflammatix, Inc. DWW: The author has no conflicts of interest to disclose. NIS: The author has received research funding from Inflammatix, Inc, and Luminos; and served as a consultant for Diagnostic Robotics and Prenosis., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose of Review: This review provides an overview of the role of microcirculation in cardiac arrest and postcardiac arrest syndrome through handheld intravital microscopy and biomarkers. It highlights the importance of microcirculatory dysfunction in postcardiac arrest outcomes and explores potential therapeutic targets., Recent Findings: Sublingual microcirculation is impaired in the early stage of postarrest and is potentially associated with increased mortality. Recent work suggests that the proportion of perfused small vessels is predictive of mortality. Microcirculatory impairment is consistently found to be independent of macrohemodynamic parameters. Biomarkers of endothelial cell injury and endothelial glycocalyx degradation are elevated in postarrest settings and may predict mortality and clinical outcomes, warranting further studies. Recent studies of exploratory therapies targeting microcirculation have shown some promise in animal models but still require significant research., Summary: Although research continues to suggest the important role that microcirculation may play in postcardiac arrest syndrome and cardiac arrest outcomes, the existing studies are still limited to draw any definitive conclusions. Further research is needed to better understand microcirculatory changes and their significance to improve cardiac arrest care and outcomes., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

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., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2024.)

The endothelial glycocalyx, a gel-like layer that lines the luminal surface of blood vessels, is composed of proteoglycans, glycoproteins, and glycosaminoglycans. The endothelial glycocalyx plays an essential role in vascular homeostasis, and its degradation in trauma and sepsis can lead to microvascular dysfunction and organ injury. While there are no proven therapies for preventing or treating endothelial glycocalyx degradation, some initial literature suggests that plasma may have a therapeutic role in trauma and sepsis patients. Overall, the literature suggesting the use of plasma as a therapy for endothelial glycocalyx degradation is non-clinical basic science or exploratory. Plasma is an established therapy in the resuscitation of patients with hemorrhage for restoration of coagulation factors. However, plasma also contains other bioactive components, including sphingosine-1 phosphate, antithrombin, and adiponectin, which may protect and restore the endothelial glycocalyx, thereby helping to maintain or restore vascular homeostasis. This narrative review begins by describing the endothelial glycocalyx in health and disease: we discuss the overlapping disease mechanisms in trauma and sepsis that lead to its damage and introduce plasma transfusion as a potential therapy for prevention and treatment of endothelial glycocalyx degradation. Second, we review the literature on plasma as an exploratory therapy for endothelial glycocalyx degradation in trauma and sepsis. Third, we discuss the safety of plasma transfusion by reviewing the adverse events associated with plasma and other blood product transfusions, and we examine modern transfusion precautions that have enhanced the safety of plasma transfusion. We conclude that the literature proposes that plasma may have the potential to prevent and treat endothelial glycocalyx degradation in trauma and sepsis, indicating the need for further research., (© 2024. The Author(s).)

Background: Early fluid management in patients with advanced chronic kidney disease (CKD) and sepsis-induced hypotension is challenging with limited evidence to support treatment recommendations. We aimed to compare an early restrictive versus liberal fluid management for sepsis-induced hypotension in patients with advanced CKD., Methods: This post-hoc analysis included patients with advanced CKD (eGFR of less than 30 mL/min/1.73 m 2 or history of end-stage renal disease on chronic dialysis) from the crystalloid liberal or vasopressor early resuscitation in sepsis (CLOVERS) trial. The primary endpoint was death from any cause before discharge home by day 90., Results: Of 1563 participants enrolled in the CLOVERS trial, 196 participants had advanced CKD (45% on chronic dialysis), with 92 participants randomly assigned to the restrictive treatment group and 104 assigned to the liberal fluid group. Death from any cause before discharge home by day 90 occurred significantly less often in the restrictive fluid group compared with the liberal fluid group (20 [21.7%] vs. 41 [39.4%], HR 0.5, 95% CI 0.29-0.85). Participants in the restrictive fluid group had more vasopressor-free days (19.7 ± 10.4 days vs. 15.4 ± 12.6 days; mean difference 4.3 days, 95% CI, 1.0-7.5) and ventilator-free days by day 28 (21.0 ± 11.8 vs. 16.5 ± 13.6 days; mean difference 4.5 days, 95% CI, 0.9-8.1)., Conclusions: In patients with advanced CKD and sepsis-induced hypotension, an early restrictive fluid strategy, prioritizing vasopressor use, was associated with a lower risk of death from any cause before discharge home by day 90 as compared with an early liberal fluid strategy., Trial Registration: NCT03434028 (2018-02-09), BioLINCC 14149., (© 2024. The Author(s).)

Background: Among critically ill adults undergoing tracheal intubation, hypoxemia increases the risk of cardiac arrest and death. The effect of preoxygenation with noninvasive ventilation, as compared with preoxygenation with an oxygen mask, on the incidence of hypoxemia during tracheal intubation is uncertain., Methods: In a multicenter, randomized trial conducted at 24 emergency departments and intensive care units in the United States, we randomly assigned critically ill adults (age, ≥18 years) undergoing tracheal intubation to receive preoxygenation with either noninvasive ventilation or an oxygen mask. The primary outcome was hypoxemia during intubation, defined by an oxygen saturation of less than 85% during the interval between induction of anesthesia and 2 minutes after tracheal intubation., Results: Among the 1301 patients enrolled, hypoxemia occurred in 57 of 624 patients (9.1%) in the noninvasive-ventilation group and in 118 of 637 patients (18.5%) in the oxygen-mask group (difference, -9.4 percentage points; 95% confidence interval [CI], -13.2 to -5.6; P<0.001). Cardiac arrest occurred in 1 patient (0.2%) in the noninvasive-ventilation group and in 7 patients (1.1%) in the oxygen-mask group (difference, -0.9 percentage points; 95% CI, -1.8 to -0.1). Aspiration occurred in 6 patients (0.9%) in the noninvasive-ventilation group and in 9 patients (1.4%) in the oxygen-mask group (difference, -0.4 percentage points; 95% CI, -1.6 to 0.7)., Conclusions: Among critically ill adults undergoing tracheal intubation, preoxygenation with noninvasive ventilation resulted in a lower incidence of hypoxemia during intubation than preoxygenation with an oxygen mask. (Funded by the U.S. Department of Defense; PREOXI ClinicalTrials.gov number, NCT05267652.)., (Copyright © 2024 Massachusetts Medical Society.)

Objectives: This study aimed to compare the different respiratory rate (RR) monitoring methods used in the emergency department (ED): manual documentation, telemetry, and capnography., Methods: This is a retrospective study using recorded patient monitoring data. The study population includes patients who presented to a tertiary care ED between January 2020 and December 2022. Inclusion and exclusion criteria were patients with simultaneous recorded RR data from all three methods and less than 10 min of recording, respectively. Linear regression and Bland-Altman analysis were performed between different methods., Results: A total of 351 patient encounters met study criteria. Linear regression yielded an R -value of 0.06 (95% confidence interval [CI] 0.00-0.12) between manual documentation and telemetry, 0.07 (95% CI 0.01-0.13) between manual documentation and capnography, and 0.82 (95% CI 0.79-0.85) between telemetry and capnography. The Bland-Altman analysis yielded a bias of -0.8 (95% limits of agreement [LOA] -12.2 to 10.6) between manual documentation and telemetry, bias of -0.6 (95% LOA -13.5 to 12.3) between manual documentation and capnography, and bias of 0.2 (95% LOA -6.2 to 6.6) between telemetry and capnography., Conclusion: There is a poor correlation between manual documentation and both automated methods, while there is relatively good agreement between the automated methods. This finding highlights the need to further investigate the methodology used by the ED staff in monitoring and documenting RR and ways to improve its reliability given that many important clinical decisions are made based on these assessments., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Authors. Journal of the American College of Emergency Physicians Open published by Wiley Periodicals LLC on behalf of American College of Emergency Physicians.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into numerous lineages with unique spike mutations and caused multiple epidemics domestically and globally. Although COVID-19 vaccines are available, new variants with the capacity for immune evasion continue to emerge. To understand and characterize the evolution of circulating SARS-CoV-2 variants in the U.S., the Centers for Disease Control and Prevention (CDC) initiated the National SARS-CoV-2 Strain Surveillance (NS3) program and has received thousands of SARS-CoV-2 clinical specimens from across the nation as part of a genotype to phenotype characterization process. Focus reduction neutralization with various antisera was used to antigenically characterize 143 SARS-CoV-2 Delta, Mu and Omicron subvariants from selected clinical specimens received between May 2021 and February 2023, representing a total of 59 unique spike protein sequences. BA.4/5 subvariants BU.1, BQ.1.1, CR.1.1, CQ.2 and BA.4/5 + D420N + K444T; BA.2.75 subvariants BM.4.1.1, BA.2.75.2, CV.1; and recombinant Omicron variants XBF, XBB.1, XBB.1.5 showed the greatest escape from neutralizing antibodies when analyzed against post third-dose original monovalent vaccinee sera. Post fourth-dose bivalent vaccinee sera provided better protection against those subvariants, but substantial reductions in neutralization titers were still observed, especially among BA.4/5 subvariants with both an N-terminal domain (NTD) deletion and receptor binding domain (RBD) substitutions K444M + N460K and recombinant Omicron variants. This analysis demonstrated a framework for long-term systematic genotype to antigenic characterization of circulating and emerging SARS-CoV-2 variants in the U.S., which is critical to assessing their potential impact on the effectiveness of current vaccines and antigen recommendations for future updates.

Importance: Emergency department (ED) visits by older adults with life-limiting illnesses are a critical opportunity to establish patient care end-of-life preferences, but little is known about the optimal screening criteria for resource-constrained EDs., Objectives: To externally validate the Geriatric End-of-Life Screening Tool (GEST) in an independent population and compare it with commonly used serious illness diagnostic criteria., Design, Setting, and Participants: This prognostic study assessed a cohort of patients aged 65 years and older who were treated in a tertiary care ED in Boston, Massachusetts, from 2017 to 2021. Patients arriving in cardiac arrest or who died within 1 day of ED arrival were excluded. Data analysis was performed from August 1, 2023, to March 27, 2024., Exposure: GEST, a logistic regression algorithm that uses commonly available electronic health record (EHR) datapoints and was developed and validated across 9 EDs, was compared with serious illness diagnoses as documented in the EHR. Serious illnesses included stroke/transient ischemic attack, liver disease, cancer, lung disease, and age greater than 80 years, among others., Main Outcomes and Measures: The primary outcome was 6-month mortality following an ED encounter. Statistical analyses included area under the receiver operating characteristic curve, calibration analyses, Kaplan-Meier survival curves, and decision curves., Results: This external validation included 82 371 ED encounters by 40 505 unique individuals (mean [SD] age, 76.8 [8.4] years; 54.3% women, 13.8% 6-month mortality rate). GEST had an external validation area under the receiver operating characteristic curve of 0.79 (95% CI, 0.78-0.79) that was stable across years and demographic subgroups. Of included encounters, 53.4% had a serious illness, with a sensitivity of 77.4% (95% CI, 76.6%-78.2%) and specificity of 50.5% (95% CI, 50.1%-50.8%). Varying GEST cutoffs from 5% to 30% increased specificity (5%: 49.1% [95% CI, 48.7%-49.5%]; 30%: 92.2% [95% CI, 92.0%-92.4%]) at the cost of sensitivity (5%: 89.3% [95% CI, 88.8-89.9]; 30%: 36.2% [95% CI, 35.3-37.1]). In a decision curve analysis, GEST outperformed serious illness criteria across all tested thresholds. When comparing patients referred to intervention by GEST with serious illness criteria, GEST reclassified 45.1% of patients with serious illness as having low risk of mortality with an observed mortality rate 8.1% and 2.6% of patients without serious illness as having high mortality risk with an observed mortality rate of 34.3% for a total reclassification rate of 25.3%., Conclusions and Relevance: The findings of this study suggest that both serious illness criteria and GEST identified older ED patients at risk for 6-month mortality, but GEST offered more useful screening characteristics. Future trials of serious illness interventions for high mortality risk in older adults may consider transitioning from diagnosis code criteria to GEST, an automatable EHR-based algorithm.

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., Competing Interests: Potential conflicts of interest. S. B. reports participating as the DSMB chair for Hamilton Ventilators, outside the submitted work. J. C. reports receiving funding from the National Institutes of Health (NIH) and Department of Defense (DoD), and a travel grant from Fisher-Paykel, outside the submitted work. S. C. reports consulting for PureTech Health in 2021–2022 and Kiniksa Pharmaceuticals in 2022, outside the submitted work. A. D. reports participating on an advisory board for ALung Technologies and being a principal investigator (PI) for the PETAL Network, outside the submitted work. C. G. G. reports consulting fees from Merck and received research support from Campbell Alliance/Syneos Health, NIH, CDC, Food and Drug Administration (FDA), and AHRQ, outside the submitted work. M. N. G. reports receiving grant funding from NIH and AHRQ for research, honorarium for giving Medicine grand rounds at Yale and Washington Healthcare, fees for DSMB for Palm trial and Regeneron trials on monoclonal antibodies, and fees for serving on scientific advisory board for Philips Healthcare on monitoring, outside the submitted work. R. G. reports consulting for Gilead Sciences, Eli Lily, GSK, Janssen, and AbbVie, being on an advisory board for Gilead Sciences, Eli Lily, GlaxoSmithKline (GSK), and AstraZeneca, speaker bureau for Pfizer and AbbVie, and gift-in-kind to institution from Gilead Sciences, outside the submitted work. N. H. reports prior grant support from Sanofi and Quidel, and current funding from Merck, outside the submitted work. A. L. reports being a consultant for Roche on a clinical trial of baloxavir, outside the submitted work. Christopher Mallow reports medical legal consulting, outside the submitted work. I. P. reports receiving grants from NHLBI, NIGMS, and Janssen Pharmaceuticals and institutional support from Regeneron, outside the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2023.)

Importance: On June 21, 2023, the Centers for Disease Control and Prevention recommended the first respiratory syncytial virus (RSV) vaccines for adults aged 60 years and older using shared clinical decision-making. Understanding the severity of RSV disease in adults can help guide this clinical decision-making., Objective: To describe disease severity among adults hospitalized with RSV and compare it with the severity of COVID-19 and influenza disease by vaccination status., Design, Setting, and Participants: In this cohort study, adults aged 18 years and older admitted to the hospital with acute respiratory illness and laboratory-confirmed RSV, SARS-CoV-2, or influenza infection were prospectively enrolled from 25 hospitals in 20 US states from February 1, 2022, to May 31, 2023. Clinical data during each patient's hospitalization were collected using standardized forms. Data were analyzed from August to October 2023., Exposures: RSV, SARS-CoV-2, or influenza infection., Main Outcomes and Measures: Using multivariable logistic regression, severity of RSV disease was compared with COVID-19 and influenza severity, by COVID-19 and influenza vaccination status, for a range of clinical outcomes, including the composite of invasive mechanical ventilation (IMV) and in-hospital death., Results: Of 7998 adults (median [IQR] age, 67 [54-78] years; 4047 [50.6%] female) included, 484 (6.1%) were hospitalized with RSV, 6422 (80.3%) were hospitalized with COVID-19, and 1092 (13.7%) were hospitalized with influenza. Among patients with RSV, 58 (12.0%) experienced IMV or death, compared with 201 of 1422 unvaccinated patients with COVID-19 (14.1%) and 458 of 5000 vaccinated patients with COVID-19 (9.2%), as well as 72 of 699 unvaccinated patients with influenza (10.3%) and 20 of 393 vaccinated patients with influenza (5.1%). In adjusted analyses, the odds of IMV or in-hospital death were not significantly different among patients hospitalized with RSV and unvaccinated patients hospitalized with COVID-19 (adjusted odds ratio [aOR], 0.82; 95% CI, 0.59-1.13; P = .22) or influenza (aOR, 1.20; 95% CI, 0.82-1.76; P = .35); however, the odds of IMV or death were significantly higher among patients hospitalized with RSV compared with vaccinated patients hospitalized with COVID-19 (aOR, 1.38; 95% CI, 1.02-1.86; P = .03) or influenza disease (aOR, 2.81; 95% CI, 1.62-4.86; P < .001)., Conclusions and Relevance: Among adults hospitalized in this US cohort during the 16 months before the first RSV vaccine recommendations, RSV disease was less common but similar in severity compared with COVID-19 or influenza disease among unvaccinated patients and more severe than COVID-19 or influenza disease among vaccinated patients for the most serious outcomes of IMV or death.