Biomarker-Concordant Steroid Administration in Severe Coronavirus Disease-2019.

BACKGROUND: Although corticosteroids have become the standard of care for patients with coronavirus disease-2019 (COVID-19) on supplemental oxygen, there is growing evidence of differential treatment response. This study aimed to evaluate if there was an association between biomarker-concordant corticosteroid treatment and COVID-19 outcomes. METHODS: This registry-based cohort study included adult COVID-19 hospitalized patients between January 2020 and December 2021 from 109 institutions. Patients with available C-reactive protein (CRP) levels within 48 h of admission were evaluated. Those on steroids before admission, stayed in the hospital for <48 h, or were not on oxygen support were excluded. Corticosteroid treatment was biomarker-concordant if given with high baseline CRP ≥150 mg/L or withheld with low CRP (<150 mg/L) and vice-versa was considered discordant (low CRP with steroids, high CRP without steroids). Hospital mortality was the primary outcome. Sensitivity analyses were conducted using varying CRP level thresholds. The model interaction was tested to determine steroid effectiveness with increasing CRP levels. RESULTS: Corticosteroid treatment was biomarker-concordant in 1778 (49%) patients and discordant in 1835 (51%). The concordant group consisted of higher-risk patients than the discordant group. After adjusting for covariates, the odds of in-hospital mortality were significantly lower in the concordant group than the discordant (odds ratio [95% confidence interval (C.I.)] = 0.71 [0.51, 0.98]). Similarly, adjusted mortality difference was significant at the CRP thresholds of 100 and 200 mg/L (odds ratio [95% C.I.] = 0.70 [0.52, 0.95] and 0.57 [0.38, 0.85], respectively), and concordant steroid use was associated with lower need for invasive ventilation for 200 mg/L threshold (odds ratio [95% C.I.] = 0.52 [0.30, 0.91]). In contrast, no outcome benefit was observed at CRP threshold of 50. When the model interaction was tested, steroids were more effective at reducing mortality as CRP levels increased. CONCLUSION: Biomarker-concordant corticosteroid treatment was associated with lower odds of in-hospital mortality in severe COVID-19.

Discharge Disposition and Loss of Independence Among Survivors of COVID-19 Admitted to Intensive Care: Results From the SCCM Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS).

OBJECTIVES: To describe incidence and risk factors of loss of previous independent living through nonhome discharge or discharge home with health assistance in survivors of intensive care unit (ICU) admission for coronavirus disease 2019 (COVID-19). DESIGN: Multicenter observational study including patients admitted to the ICU from January 2020 till June 30, 2021. HYPOTHESIS: We hypothesized that there is a high risk of nonhome discharge in patients surviving ICU admission due to COVID-19. SETTING: Data were included from 306 hospitals in 28 countries participating in the SCCM Discovery Viral Infection and Respiratory Illness Universal Study COVID-19 registry. PATIENTS: Previously independently living adult ICU survivors of COVID-19. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was nonhome discharge. Secondary outcome was the requirement of health assistance among patients who were discharged home. Out of 10 820 patients, 7101 (66%) were discharged alive; 3791 (53%) of these survivors lost their previous independent living status, out of those 2071 (29%) through nonhome discharge, and 1720 (24%) through discharge home requiring health assistance. In adjusted analyses, loss of independence on discharge among survivors was predicted by patient age ≥ 65 years (adjusted odds ratio [aOR] 2.78, 95% confidence interval [CI] 2.47-3.14, P < .0001), former and current smoking status (aOR 1.25, 95% CI 1.08-1.46, P = .003 and 1.60 (95% CI 1.18-2.16), P = .003, respectively), substance use disorder (aOR 1.52, 95% CI 1.12-2.06, P = .007), requirement for mechanical ventilation (aOR 4.17, 95% CI 3.69-4.71, P < .0001), prone positioning (aOR 1.19, 95% CI 1.03-1.38, P = .02), and requirement for extracorporeal membrane oxygenation (aOR 2.28, 95% CI 1.55-3.34, P < .0001). CONCLUSIONS: More than half of ICU survivors hospitalized for COVID-19 are unable to return to independent living status, thereby imposing a significant secondary strain on health care systems worldwide.

Development and Validation of an Acute Respiratory Distress Syndrome Prediction Model in Coronavirus Disease 2019: Updated Lung Injury Prediction Score.

OBJECTIVE: To develop and validate an updated lung injury prediction score for coronavirus disease 2019 (COVID-19) (c-LIPS) tailored for predicting acute respiratory distress syndrome (ARDS) in COVID-19. PATIENTS AND METHODS: This was a registry-based cohort study using the Viral Infection and Respiratory Illness Universal Study. Hospitalized adult patients between January 2020 and January 2022 were screened. Patients who qualified for ARDS within the first day of admission were excluded. Development cohort consisted of patients enrolled from participating Mayo Clinic sites. The validation analyses were performed on remaining patients enrolled from more than 120 hospitals in 15 countries. The original lung injury prediction score (LIPS) was calculated and enhanced using reported COVID-19-specific laboratory risk factors, constituting c-LIPS. The main outcome was ARDS development and secondary outcomes included hospital mortality, invasive mechanical ventilation, and progression in WHO ordinal scale. RESULTS: The derivation cohort consisted of 3710 patients, of whom 1041 (28.1%) developed ARDS. The c-LIPS discriminated COVID-19 patients who developed ARDS with an area under the curve (AUC) of 0.79 compared with original LIPS (AUC, 0.74; P<.001) with good calibration accuracy (Hosmer-Lemeshow P=.50). Despite different characteristics of the two cohorts, the c-LIPS's performance was comparable in the validation cohort of 5426 patients (15.9% ARDS), with an AUC of 0.74; and its discriminatory performance was significantly higher than the LIPS (AUC, 0.68; P<.001). The c-LIPS's performance in predicting the requirement for invasive mechanical ventilation in derivation and validation cohorts had an AUC of 0.74 and 0.72, respectively. CONCLUSION: In this large patient sample c-LIPS was successfully tailored to predict ARDS in COVID-19 patients.

At the intersection of trust and mistrust: A qualitative analysis of motivators and barriers to research participation at a safety-net hospital.

INTRODUCTION: The underrepresentation of Black, Indigenous, and People of Color (BIPOC) individuals in healthcare research limits generalizability and contributes to healthcare inequities. Existing barriers and attitudes toward research participation must be addressed to increase the representation of safety net and other underserved populations. METHODS: We conducted semi-structured qualitative interviews with patients at an urban safety net hospital, focusing on facilitators, barriers, motivators, and preferences for research participation. We conducted direct content analysis guided by an implementation framework and used rapid analysis methods to generate final themes. RESULTS: We completed 38 interviews and identified six major themes related to preferences for engagement in research participation: (1) wide variation in research recruitment preferences; (2) logistical complexity negatively impacts willingness to participate; (3) risk contributes to hesitation toward research participation; (4) personal/community benefit, interest in study topic, and compensation serve as motivators for research participation; (5) continued participation despite reported shortcomings of informed consent process; and (6) mistrust could be overcome by relationship or credibility of information sources. CONCLUSION: Despite barriers to participation in research studies among safety-net populations, there are also facilitators that can be implemented to increase knowledge and comprehension, ease of participation, and willingness to join research studies. Study teams should vary recruitment and participation methods to ensure equal access to research opportunities. PATIENT/PUBLIC CONTRIBUTION: Our analysis methods and study progress were presented to individuals within the Boston Medical Center healthcare system. Through this process community engagement specialists, clinical experts, research directors, and others with significant experience working with safety-net populations supported data interpretation and provided recommendations for action following the dissemination of data.

Practice Changes Among Patients Without COVID-19 Receiving Mechanical Ventilation During the Early COVID-19 Pandemic.

The COVID-19 pandemic led to rapid changes in care delivery for critically ill patients, due to factors including increased numbers of ICU patients, shifting staff roles, and changed care locations. As these changes may have impacted the care of patients without COVID-19, we assessed changes in common ICU practices for mechanically ventilated patients with non-COVID acute respiratory failure at the onset of and during the COVID-19 pandemic. DESIGN: Interrupted time series analysis, adjusted for seasonality and autocorrelation where present, evaluating trends in common ICU practices prior to the pandemic (March 2016 to February 2020), at the onset of the pandemic (April 2020) and intra-pandemic (April 2020 to December 2020). SETTING: Premier Healthcare Database, containing data from 25% of U.S. discharges from January 1, 2016, to December 31, 2020. PATIENTS: Patients without COVID-19 receiving mechanical ventilation for acute respiratory failure. INTERVENTIONS: We assessed monthly rates of chest radiograph (CXR), chest CT scans, lower extremity noninvasive vascular testing (LENI), bronchoscopy, arterial catheters, and central venous catheters. MEASUREMENTS AND MAIN RESULTS: We identified 742,096 mechanically ventilated patients without COVID-19 at 545 hospitals. At the onset of the pandemic, CXR (-0.5% [-0.9% to -0.2%; p = 0.001]), LENI (LENI: -2.1% [-3.3% to -0.9%; p = 0.001]), and bronchoscopy rates (-1.0% [-1.5% to -0.6%; p < 0.001]) decreased; use of chest CT increased (1.5% [0.5-2.5%; p = 0.006]). Use of arterial lines and central venous catheters did not change significantly. Intra-pandemic, LENI (0.5% [0.3-0.7%; p < 0.001]/mo) and bronchoscopy (0.1% [0.05-0.2%; p < 0.001]/mo) trends increased relative to pre-pandemic trends, while the remainder of practices did not change significantly. CONCLUSIONS: We observed several statistically significant changes to practice patterns among patients without COVID-19 early during the pandemic. However, most of the changes were small or temporary, suggesting that routine practices in the care of mechanically ventilated patients in the ICU was not drastically affected by the pandemic.

Circulating neutrophil extracellular trap (NET)-forming 'rogue' neutrophil subset, immunotype [DEspR + CD11b +], mediate multi-organ failure in COVID-19-an observational study.

Background: Cumulative research show association of neutrophils and neutrophil extracellular traps (NETs) with poor outcomes in severe COVID-19. However, to date, there is no curative intent therapy able to block neutrophil/NETs-mediated progression of multi-organ dysfunction. Because of emerging neutrophil heterogeneity, the study of subsets of circulating NET-forming neutrophils [NET + Ns] as mediators of multi-organ failure progression among patients with COVID-19 is critical to identification of therapeutic targets. Methods: We conducted a prospective observational study of circulating levels of CD11b + [NET + N] immunotyped for dual endothelin-1/signal peptide receptor (DEspR ±) expression by quantitative immunofluorescence-cytology and causal mediation analysis. In 36 consented adults hospitalized with mod-severe COVID-19, May to September 2020, we measured acute multi-organ failure via SOFA-scores and respiratory failure via SaO2/FiO2 (SF)-ratio at time points t1 (average 5.5 days from ICU/hospital admission) and t2 (the day before ICU-discharge or death), and ICU-free days at day28 (ICUFD). Circulating absolute neutrophil counts (ANC) and [NET + N] subset-specific counts were measured at t1. Spearman correlation and causal mediation analyses were conducted. Results: Spearman correlation analyses showed correlations of t1-SOFA with t2-SOFA (rho r S = 0.80) and ICUFD (r S = -0.76); circulating DEspR + [NET + Ns] with t1-SOFA (r S = 0.71), t2-SOFA (r S = 0.62), and ICUFD (r S = -0.63), and ANC with t1-SOFA (r S = 0.71), and t2-SOFA (r S = 0.61).Causal mediation analysis identified DEspR + [NET + Ns] as mediator of 44.1% [95% CI:16.5,110.6] of the causal path between t1-SOFA (exposure) and t2-SOFA (outcome), with 46.9% [15.8,124.6] eliminated when DEspR + [NET + Ns] were theoretically reduced to zero. Concordantly, DEspR + [NET + Ns] mediated 47.1% [22.0,72.3%] of the t1-SOFA to ICUFD causal path, with 51.1% [22.8,80.4%] eliminated if DEspR + [NET + Ns] were reduced to zero. In patients with t1-SOFA > 1, the indirect effect of a hypothetical treatment eliminating DEspR + [NET + Ns] projected a reduction of t2-SOFA by 0.98 [0.29,2.06] points and ICUFD by 3.0 [0.85,7.09] days. In contrast, there was no significant mediation of SF-ratio through DEspR + [NET + Ns], and no significant mediation of SOFA-score through ANC. Conclusions: Despite equivalent correlations, DEspR + [NET + Ns], but not ANC, mediated progression of multi-organ failure in acute COVID-19, and its hypothetical reduction is projected to improve ICUFD. These translational findings warrant further studies of DEspR + [NET + Ns] as potential patient-stratifier and actionable therapeutic target for multi-organ failure in COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1186/s41231-023-00143-x.

A multisite exploration of the association between critical care implementation factors and clinical outcomes during the COVID-19 pandemic.

Background: Little is known about strategies to implement new critical care practices in response to COVID-19. Moreover, the association between differing implementation climates and COVID-19 clinical outcomes has not been examined. The purpose of this study was to evaluate the relationship between implementation determinants and COVID-19 mortality rates. Methods: We used mixed methods guided by the Consolidated Framework for Implementation Research (CFIR). Semi-structured qualitative interviews were conducted with critical care leaders and analyzed to rate the influence of CFIR constructs on the implementation of new care practices. Qualitative and quantitative comparisons of CFIR construct ratings were performed between hospital groups with low- versus high-mortality rates. Results: We found associations between various implementation factors and clinical outcomes of critically ill COVID-19 patients. Three CFIR constructs (implementation climate, leadership engagement, and engaging staff) had both qualitative and statistically significant quantitative correlations with mortality outcomes. An implementation climate governed by a trial-and-error approach was correlated with high COVID-19 mortality, while leadership engagement and engaging staff were correlated with low mortality. Another three constructs (needs of patient; organizational incentives and rewards; and engaging implementation leaders) were qualitatively different across mortality outcome groups, but these differences were not statistically significant. Conclusions: Improving clinical outcomes during future public health emergencies will require reducing identified barriers associated with high mortality and harnessing salient facilitators associated with low mortality. Our findings suggest that collaborative and engaged leadership styles that promote the integration of new yet evidence-based critical care practices best support COVID-19 patients and contribute to lower mortality.

Facilitators and barriers to the implementation of new critical care practices during COVID-19: a multicenter qualitative study using the Consolidated Framework for Implementation Research (CFIR).

BACKGROUND: The COVID-19 pandemic produced unprecedented demands and rapidly changing evidence and practices within critical care settings. The purpose of this study was to identify factors and strategies that hindered and facilitated effective implementation of new critical care practices and policies in response to the pandemic. METHODS: We used a cross-sectional, qualitative study design to conduct semi-structured in-depth interviews with critical care leaders across the United States. The interviews were audio-taped and professionally transcribed verbatim. Guided by the Consolidated Framework for Implementation Research (CFIR), three qualitative researchers used rapid analysis methods to develop relevant codes and identify salient themes. RESULTS: Among the 17 hospitals that agreed to participate in this study, 31 clinical leaders were interviewed. The CFIR-driven rapid analysis of the interview transcripts generated 12 major themes, which included six implementation facilitators (i.e., factors that promoted the implementation of new critical care practices) and six implementation barriers (i.e., factors that hindered the implementation of new critical care practices). These themes spanned the five CFIR domains (Intervention Characteristics, Outer Setting, Inner Setting, Characteristics of Individuals, and Process) and 11 distinct CFIR constructs. Salient facilitators to implementation efforts included staff resilience, commitment, and innovation, which were supported through collaborative feedback and decision-making mechanisms between leadership and frontline staff. Major identified barriers included lack of access to reliable and transferable information, available resources, uncollaborative leadership and communication styles. CONCLUSIONS: Through applying the CFIR to organize and synthesize our qualitative data, this study revealed important insights into implementation determinants that influenced the uptake of new critical care practices during COVID-19. As the pandemic continues to burden critical care units, clinical leaders should consider emulating the effective change management strategies identified. The cultivation of streamlined, engaging, and collaborative leadership and communication mechanisms not only supported implementation of new care practices across sites, but it also helped reduce salient implementation barriers, particularly resource and staffing shortages. Future critical care implementation studies should seek to capitalize on identified facilitators and reduce barriers.

Coronavirus Disease 2019 in Pediatric Oncology Patients: A Matched-Cohort Analysis of the SCCM Discovery Viral Infection and Respiratory Illness Universal Study COVID-19 Registry.

BACKGROUND: There is a paucity of multicenter data describing the impact of coronavirus disease 2019 (COVID-19) on hospitalized pediatric oncology patients. Using a large, multicenter, Society of Critical Care Medicine (SCCM) Discovery Viral Infection and Respiratory Illness University Study (VIRUS) database, we aimed at assessing outcomes of COVID-19 infection in this population. METHOD: This is a matched-cohort study involving children below 18 years of age hospitalized with COVID-19 between March 2020 and January 2021. Using the VIRUS; COVID-19 Registry database, children with oncologic diseases were compared with propensity score matched (age groups, sex, race, and ethnicity) cohort of children without oncologic diseases for the prevalence of Multisystem Inflammatory Syndrome in Children (MIS-C), intensive care unit (ICU) admission, interventions, hospital, and ICU length of stay. RESULTS: The number of children in the case and control groups was 45 and 180, respectively. ICU admission rate was similar in both groups ([47.7 vs 51.7%], P =0.63). The proportion of children requiring noninvasive and invasive mechanical ventilation, and its duration were similar between groups, same as hospital mortality. Interestingly, MIS-C was significantly lower in the oncology group compared with the control (2.4 vs 24.6%; P =0.0002). CONCLUSIONS: In this study using a multicenter VIRUS database, ICU admission rate, interventions, and outcomes of COVID-19 were similar in children with the oncologic disease compared with control patients. The incidence of MIS-C is lower in oncologic patients.

Hospital Variation in Management and Outcomes of Acute Respiratory Distress Syndrome Due to COVID-19.

OBJECTIVES: To describe hospital variation in use of "guideline-based care" for acute respiratory distress syndrome (ARDS) due to COVID-19. DESIGN: Retrospective, observational study. SETTING: The Society of Critical Care Medicine's Discovery Viral Infection and RESPIRATORY ILLNESS UNIVERSAL STUDY COVID-19 REGISTRY. PATIENTS: Adult patients with ARDS due to COVID-19 between February 15, 2020, and April 12, 2021. INTERVENTIONS: Hospital-level use of "guideline-based care" for ARDS including low-tidal-volume ventilation, plateau pressure less than 30 cm H2O, and prone ventilation for a Pao2/Fio2 ratio less than 100. MEASUREMENTS AND MAIN RESULTS: Among 1,495 adults with COVID-19 ARDS receiving care across 42 hospitals, 50.4% ever received care consistent with ARDS clinical practice guidelines. After adjusting for patient demographics and severity of illness, hospital characteristics, and pandemic timing, hospital of admission contributed to 14% of the risk-adjusted variation in "guideline-based care." A patient treated at a randomly selected hospital with higher use of guideline-based care had a median odds ratio of 2.0 (95% CI, 1.1-3.4) for receipt of "guideline-based care" compared with a patient receiving treatment at a randomly selected hospital with low use of recommended therapies. Median-adjusted inhospital mortality was 53% (interquartile range, 47-62%), with a nonsignificantly decreased risk of mortality for patients admitted to hospitals in the highest use "guideline-based care" quartile (49%) compared with the lowest use quartile (60%) (odds ratio, 0.7; 95% CI, 0.3-1.9; p = 0.49). CONCLUSIONS: During the first year of the COVID-19 pandemic, only half of patients received "guideline-based care" for ARDS management, with wide practice variation across hospitals. Strategies that improve adherence to recommended ARDS management strategies are needed.

Variations in Administrative Approvals During the COVID-19 Pandemic at Participating Sites in the Society of Critical Care Medicine Discovery Network Viral Infection and Respiratory Illness Universal Study: COVID-19 Registry: A Cross-Sectional Study.

There is a paucity of literature regarding administrative approvals required for clinical studies during a pandemic. We aimed to evaluate variation in duration of administrative approvals within the Viral Infection and Respiratory illness Universal Study (VIRUS): A Global COVID-19 Registry. DESIGN SETTING AND SUBJECTS: Survey analysis of 188 investigators who participated in the VIRUS: COVID-19 registry, a prospective, observational global registry database of 287 sites. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: For each study site approved through December 8, 2020, we assessed the duration in days: 1) from institutional review board (IRB) submission to IRB approval, 2) from IRB approval to Research Electronic Data Capture (REDCap) access, 3) from REDCap access to first patient data entry in REDCap, and 4) total duration from IRB submission to first patient data entry in REDCap. Analysis of variance and Wilcoxon rank-sum test were used to compare time durations. Of 287 sites, 188 sites (United States = 155, non-United States = 33) provided complete administrative data. There was considerable variability in duration from IRB submission to first patient data entry with median (interquartile range) of 28 days (16-50 d), with differences not significantly different by country (United States: 30 [17-50] vs non-United States: 23 d [8-46 d]; p = 0.08) or previous "multisite trial experience" (experienced: 27 [15-51] vs not experienced: 29 d [13-47 d]; p = 0.67). The U.S. sites had a higher proportion of female principal investigators (n = 77; 50%), compared with non-U.S. sites (n = 7; 21%; p = 0.002). Non-U.S. sites had a significantly shorter time to first patient data entry after REDCap access: 7 (1-28) versus 3 days (1-6 d) (p = 0.02). CONCLUSIONS: In this Society of Critical Care Medicine global VIRUS: COVID-19 Registry, we identified considerable variability in time from IRB submission to first patient data entry with no significant differences by country or prior multicenter trial experience. However, there was a significant difference between US and non-U.S. sites in the time from REDCap access to first data entry.

The Association of Latitude and Altitude with COVID-19 Symptoms: A VIRUS: COVID-19 Registry Analysis.

Background: Better delineation of COVID-19 presentations in different climatological conditions might assist with prompt diagnosis and isolation of patients. Objectives: To study the association of latitude and altitude with COVID-19 symptomatology. Methods: This observational cohort study included 12267 adult COVID-19 patients hospitalized between 03/2020 and 01/2021 at 181 hospitals in 24 countries within the SCCM Discovery VIRUS: COVID-19 Registry. The outcome was symptoms at admission, categorized as respiratory, gastrointestinal, neurological, mucocutaneous, cardiovascular, and constitutional. Other symptoms were grouped as atypical. Multivariable regression modeling was performed, adjusting for baseline characteristics. Models were fitted using generalized estimating equations to account for the clustering. Results: The median age was 62 years, with 57% males. The median age and percentage of patients with comorbidities increased with higher latitude. Conversely, patients with comorbidities decreased with elevated altitudes. The most common symptoms were respiratory (80%), followed by constitutional (75%). Presentation with respiratory symptoms was not associated with the location. After adjustment, at lower latitudes (<30º), patients presented less commonly with gastrointestinal symptoms (p<.001, odds ratios for 15º, 25º, and 30º: 0.32, 0.81, and 0.98, respectively). Atypical symptoms were present in 21% of the patients and showed an association with altitude (p=.026, odds ratios for 75, 125, 400, and 600 meters above sea level: 0.44, 0.60, 0.84, and 0.77, respectively). Conclusions: We observed geographic variability in symptoms of COVID-19 patients. Respiratory symptoms were most common but were not associated with the location. Gastrointestinal symptoms were less frequent in lower latitudes. Atypical symptoms were associated with higher altitude.

Association of Early Steroid Administration With Outcomes of Children Hospitalized for COVID-19 Without Multisystem Inflammatory Syndrome in Children.

Importance: There is limited evidence for therapeutic options for pediatric COVID-19 outside of multisystem inflammatory syndrome in children (MIS-C). Objective: To determine whether the use of steroids within 2 days of admission for non-MIS-C COVID-19 in children is associated with hospital length of stay (LOS). The secondary objective was to determine their association with intensive care unit (ICU) LOS, inflammation, and fever defervescence. Design, Setting, and Participants: This cohort study analyzed data retrospectively for children (<18 years) who required hospitalization for non-MIS-C COVID-19. Data from March 2020 through September 2021 were provided by 58 hospitals in 7 countries who participate in the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) COVID-19 registry. Exposure: Administration of steroids within 2 days of admission. Main Outcomes and Measures: Length of stay in the hospital and ICU. Adjustment for confounders was done by mixed linear regression and propensity score matching. Results: A total of 1163 patients met inclusion criteria and had a median (IQR) age of 7 years (0.9-14.3). Almost half of all patients (601/1163, 51.7%) were male, 33.8% (392/1163) were non-Hispanic White, and 27.9% (324/1163) were Hispanic. Of the study population, 184 patients (15.8%) received steroids within 2 days of admission, and 979 (84.2%) did not receive steroids within the first 2 days. Among 1163 patients, 658 (56.5%) required respiratory support during hospitalization. Overall, patients in the steroids group were older and had greater severity of illness, and a larger proportion required respiratory and vasoactive support. On multivariable linear regression, after controlling for treatment with remdesivir within 2 days, country, race and ethnicity, obesity and comorbidity, number of abnormal inflammatory mediators, age, bacterial or viral coinfection, and disease severity according to ICU admission within first 2 days or World Health Organization ordinal scale of 4 or higher on admission, with a random intercept for the site, early steroid treatment was not significantly associated with hospital LOS (exponentiated coefficient, 0.94; 95% CI, 0.81-1.09; P = .42). Separate analyses for patients with an LOS of 2 days or longer (n = 729), those receiving respiratory support at admission (n = 286), and propensity score-matched patients also showed no significant association between steroids and LOS. Early steroid treatment was not associated with ICU LOS, fever defervescence by day 3, or normalization of inflammatory mediators. Conclusions and Relevance: Steroid treatment within 2 days of hospital admission in a heterogeneous cohort of pediatric patients hospitalized for COVID-19 without MIS-C did not have a statistically significant association with hospital LOS.

SARS-CoV-2 With Concurrent Respiratory Viral Infection as a Risk Factor for a Higher Level of Care in Hospitalized Pediatric Patients.

OBJECTIVE: As of early 2021, there have been over 3.5 million pediatric cases of SARS-CoV-2, including 292 pediatric deaths in the United States. Although most pediatric patients present with mild disease, they are still at risk for developing significant morbidity requiring hospitalization and intensive care unit (ICU) level of care. This study was performed to evaluate if the presence of concurrent respiratory viral infections in pediatric patients admitted to the hospital with SARS-CoV-2 was associated with an increased rate of ICU level of care. DESIGN: A multicenter, international, noninterventional, cross-sectional study using data provided through The Society of Critical Care Medicine Discovery Network Viral Infection and Respiratory Illness Universal Study database. SETTING: The medical ward and ICU of 67 participating hospitals. PATIENTS: Pediatric patients younger than 18 years hospitalized with SARS-CoV-2. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 922 patients were included. Among these patients, 391 required ICU level care and 31 had concurrent non-SARS-CoV-2 viral coinfection. In a multivariate analysis, after accounting for age, positive blood culture, positive sputum culture, preexisting chronic medical conditions, the presence of a viral respiratory coinfection was associated with need for ICU care (odds ratio, 3.6; 95% confidence interval, 1.6-9.4; P < 0.01). CONCLUSIONS: This study demonstrates an association between concurrent SARS-CoV-2 infection with viral respiratory coinfection and the need for ICU care. Further research is needed to identify other risk factors that can be used to derive and validate a risk-stratification tool for disease severity in pediatric patients with SARS-CoV-2.

Pre-hospital Aspirin Use and Patient Outcomes in COVID-19: Results from the International Viral Infection and Respiratory Illness Universal Study (VIRUS).

INTRODUCTION: The goal of this investigation is to assess the association between prehospital use of aspirin (ASA) and patient-centered outcomes in a large global cohort of hospitalized COVID-19 patients. METHODS: This study utilizes data from the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) Registry. Adult patients hospitalized from February 15th, 2020, to September 30th, 2021, were included. Multivariable regression analyses were utilized to assess the association between pre-hospital use of ASA and the primary outcome of overall hospital mortality. RESULTS: 21,579 patients were included from 185 hospitals (predominantly US-based, 71.3%), with 4691 (21.7%) receiving pre-hospital ASA. Patients receiving ASA, compared to those without pre-admission ASA use, were generally older (median 70 vs. 59 years), more likely to be male (58.7 vs. 56.0%), caucasian (57.4 vs. 51.6%), and more commonly had higher rates of medical comorbidities. In multivariable analyses, patients receiving pre-hospital ASA had lower mortality (HR: 0.89, 95% CI 0.82-0.97, p=0.01) and reduced hazard for progression to severe disease or death (HR: 0.91, 95% CI 0.84-0.99, p=0.02) and more hospital free days (1.00 days, 95% CI 0.66-1.35, p=0.01) compared to those without pre-hospital ASA use. The overall direction and significance of the results remained the same in sensitivity analysis, after adjusting the multivariable model for time since pandemic. CONCLUSIONS: In this large international cohort, pre-hospital use of ASA was associated with a lower hazard for death in hospitalized patients with COVID-19. Randomized controlled trials may be warranted to assess the utility of pre-hospital use of ASA.

Inhaled Nitric Oxide vs Epoprostenol During Acute Respiratory Failure: An Observational Target Trial Emulation.

BACKGROUND: The inhaled vasodilators nitric oxide and epoprostenol may be initiated to improve oxygenation in mechanically ventilated patients with severe acute respiratory failure (ARF); however, practice patterns and head-to-head comparisons of effectiveness are unclear. RESEARCH QUESTION: What are the practice patterns and comparative effectiveness for inhaled nitric oxide and epoprostenol in severe ARF? STUDY DESIGN AND METHODS: Using a large US database (Premier Healthcare Database), we identified adult patients with ARF or ARDS who were mechanically ventilated and started on inhaled nitric oxide, epoprostenol, or both. Leveraging large hospital variation in the choice of initial inhaled vasodilator, we compared the effectiveness of inhaled nitric oxide with that of epoprostenol by limiting analysis to patients admitted to hospitals that exclusively used either inhaled nitric oxide or epoprostenol. The primary outcome of successful extubation was modeled using multivariate Fine-Grey competing risk (death or hospice discharge) time-to-event models. RESULTS: Among 11,200 patients (303 hospitals), 6,366 patients (56.8%) received inhaled nitric oxide first, 4,720 patients (42.1%) received inhaled epoprostenol first, and 114 patients (1.0%) received both therapies on the same day. One hundred four hospitals (34.3%; 1,666 patients) exclusively used nitric oxide and 118 hospitals (38.9%; 1,812 patients) exclusively used epoprostenol. No differences were found in the likelihood of successful extubation between patients admitted to nitric oxide-only hospitals vs those admitted to epoprostenol-only hospitals (subdistribution hazard ratio, 0.97; 95% CI, 0.80-1.18). Also no differences were found in total hospital costs or death. Results were robust to multiple sensitivity analyses. INTERPRETATION: Large variation exists in the use of initial inhaled vasodilator for respiratory failure across US hospitals. Comparative effectiveness analyses identified no differences in outcomes based on inhaled vasodilator type.

Association of Renin Angiotensin Aldosterone System Inhibitors and Outcomes of Hospitalized Patients With COVID-19.

OBJECTIVES: To determine the association of prior use of renin-angiotensin-aldosterone system inhibitors (RAASIs) with mortality and outcomes in hospitalized patients with COVID-19. DESIGN: Retrospective observational study. SETTING: Multicenter, international COVID-19 registry. SUBJECTS: Adult hospitalized COVID-19 patients on antihypertensive agents (AHAs) prior to admission, admitted from March 31, 2020, to March 10, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were compared between three groups: patients on RAASIs only, other AHAs only, and those on both medications. Multivariable logistic and linear regressions were performed after controlling for prehospitalization characteristics to estimate the effect of RAASIs on mortality and other outcomes during hospitalization. Of 26,652 patients, 7,975 patients were on AHAs prior to hospitalization. Of these, 1,542 patients (19.3%) were on RAASIs only, 3,765 patients (47.2%) were on other AHAs only, and 2,668 (33.5%) patients were on both medications. Compared with those taking other AHAs only, patients on RAASIs only were younger (mean age 63.3 vs 66.9 yr; p < 0.0001), more often male (58.2% vs 52.4%; p = 0.0001) and more often White (55.1% vs 47.2%; p < 0.0001). After adjusting for age, gender, race, location, and comorbidities, patients on combination of RAASIs and other AHAs had higher in-hospital mortality than those on RAASIs only (odds ratio [OR] = 1.28; 95% CI [1.19-1.38]; p < 0.0001) and higher mortality than those on other AHAs only (OR = 1.09; 95% CI [1.03-1.15]; p = 0.0017). Patients on RAASIs only had lower mortality than those on other AHAs only (OR = 0.87; 95% CI [0.81-0.94]; p = 0.0003). Patients on ACEIs only had higher mortality compared with those on ARBs only (OR = 1.37; 95% CI [1.20-1.56]; p < 0.0001). CONCLUSIONS: Among patients hospitalized for COVID-19 who were taking AHAs, prior use of a combination of RAASIs and other AHAs was associated with higher in-hospital mortality than the use of RAASIs alone. When compared with ARBs, ACEIs were associated with significantly higher mortality in hospitalized COVID-19 patients.