Bayesian response adaptive randomization design with a composite endpoint of mortality and morbidity.

Allocating patients to treatment arms during a trial based on the observed responses accumulated up to the decision point, and sequential adaptation of this allocation, could minimize the expected number of failures or maximize total benefits to patients. In this study, we developed a Bayesian response-adaptive randomization (RAR) design targeting the endpoint of organ support-free days (OSFD) for patients admitted to the intensive care units. The OSFD is a mixture of mortality and morbidity assessed by the number of days of free of organ support within a predetermined post-randomization time-window. In the past, researchers treated OSFD as an ordinal outcome variable where the lowest category is death. We propose a novel RAR design for a composite endpoint of mortality and morbidity, for example, OSFD, by using a Bayesian mixture model with a Markov chain Monte Carlo sampling to estimate the posterior probability distribution of OSFD and determine treatment allocation ratios at each interim. Simulations were conducted to compare the performance of our proposed design under various randomization rules and different alpha spending functions. The results show that our RAR design using Bayesian inference allocated more patients to the better performing arm(s) compared to other existing adaptive rules while assuring adequate power and type I error rate control across a range of plausible clinical scenarios.

Nirmatrelvir/Ritonavir Use and Hospitalizations or Death in a Previously Uninfected Nonhospitalized High-Risk Population With COVID-19: A Matched Cohort Study.

OBJECTIVE: To determine the association of nirmatrelvir/ritonavir (NMV/r) with hospitalization or death within 30 days as compared with untreated controls previously uninfected and nonhospitalized. METHODS: We used a matched cohort design using inverse probability of treatment weight (IPTW). Individuals prescribed NMV/r within 3 days of COVID-19 diagnosis were compared with IPTW-based untreated controls. Variables for IPTW included age, race, sex, body mass index, geographic location, vaccination status, and multiple comorbidities. Additional analyses were conducted on NMV/r-treated and propensity score-matched untreated controls. RESULTS: Among 7615 individuals prescribed NMV/r and 62 077 controls identified between 1 January 2022 and 25 February 2023, the risk of hospitalization/death was lower among NMV/r-treated persons vs untreated controls (243 vs 3468 events; absolute risk difference [ARD], -2.36 [95% CI, -2.57 to -2.14]). The difference was significant for those >60 and ≤60 years old (ARD, -3.86 [95% CI, -4.19 to -3.54] vs -0.27 [95% CI, -0.51 to -0.03]) and for persons asymptomatic and symptomatic (ARD, -7.09 [95% CI, -7.62 to -6.55] vs -1.46 [95% CI, -1.66 to -1.25]). Significant benefit was observed among individuals unvaccinated and vaccinated, with or without a booster dose. CONCLUSIONS: NMV/r is associated with a significant reduction in 30-day hospitalization or death among individuals previously uninfected and nonhospitalized.

Molnupiravir Use and 30-Day Hospitalizations or Death in a Previously Uninfected Nonhospitalized High-risk Population With COVID-19.

BACKGROUND: Clinical benefit of molnupiravir (MPV) in coronavirus disease 2019 (COVID-19)-infected subpopulations is unclear. METHODS: We used a matched cohort study design to determine the rate of hospitalization or death within 30 days of COVID-19 diagnosis among MPV treated and untreated controls. Participants were nonhospitalized, previously uninfected Veterans with a first confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection between 1 January and 31 August 2022, who were prescribed MPV within 3 days of COVID-19 diagnosis, and matched individuals who were not prescribed MPV. RESULTS: Among 1459 matched pairs, the incidence of hospitalization/death was not different among MPV treated versus untreated controls (48 vs 44 cases; absolute risk difference [ARD], 0.27; 95% confidence interval [CI], -.94 to 1.49). No benefit was observed among those >60 or ≤60 years old (ARD, 0.27; 95% CI, -1.25 to 1.79 vs ARD, -0.29; 95% CI, -1.22 to 1.80), those with specific comorbidities, or by vaccination status. A significant benefit was observed in asymptomatic but not in symptomatic persons (ARD, -2.80; 95% CI, -4.74 to -.87 vs ARD, 1.12; 95% CI -.31 to 2.55). Kaplan-Meier curves did not show a difference in proportion of persons who were hospitalized or died among MPV treated compared with untreated controls (logrank P = .7). CONCLUSIONS: MPV was not associated with a reduction in hospitalization or death within 30 days of COVID-19 diagnosis. A subgroup of patients presenting without symptoms experienced a benefit.

Heterogeneous Treatment Effects of Therapeutic-Dose Heparin in Patients Hospitalized for COVID-19.

Importance: Randomized clinical trials (RCTs) of therapeutic-dose heparin in patients hospitalized with COVID-19 produced conflicting results, possibly due to heterogeneity of treatment effect (HTE) across individuals. Better understanding of HTE could facilitate individualized clinical decision-making. Objective: To evaluate HTE of therapeutic-dose heparin for patients hospitalized for COVID-19 and to compare approaches to assessing HTE. Design, Setting, and Participants: Exploratory analysis of a multiplatform adaptive RCT of therapeutic-dose heparin vs usual care pharmacologic thromboprophylaxis in 3320 patients hospitalized for COVID-19 enrolled in North America, South America, Europe, Asia, and Australia between April 2020 and January 2021. Heterogeneity of treatment effect was assessed 3 ways: using (1) conventional subgroup analyses of baseline characteristics, (2) a multivariable outcome prediction model (risk-based approach), and (3) a multivariable causal forest model (effect-based approach). Analyses primarily used bayesian statistics, consistent with the original trial. Exposures: Participants were randomized to therapeutic-dose heparin or usual care pharmacologic thromboprophylaxis. Main Outcomes and Measures: Organ support-free days, assigning a value of -1 to those who died in the hospital and the number of days free of cardiovascular or respiratory organ support up to day 21 for those who survived to hospital discharge; and hospital survival. Results: Baseline demographic characteristics were similar between patients randomized to therapeutic-dose heparin or usual care (median age, 60 years; 38% female; 32% known non-White race; 45% Hispanic). In the overall multiplatform RCT population, therapeutic-dose heparin was not associated with an increase in organ support-free days (median value for the posterior distribution of the OR, 1.05; 95% credible interval, 0.91-1.22). In conventional subgroup analyses, the effect of therapeutic-dose heparin on organ support-free days differed between patients requiring organ support at baseline or not (median OR, 0.85 vs 1.30; posterior probability of difference in OR, 99.8%), between females and males (median OR, 0.87 vs 1.16; posterior probability of difference in OR, 96.4%), and between patients with lower body mass index (BMI <30) vs higher BMI groups (BMI ≥30; posterior probability of difference in ORs >90% for all comparisons). In risk-based analysis, patients at lowest risk of poor outcome had the highest propensity for benefit from heparin (lowest risk decile: posterior probability of OR >1, 92%) while those at highest risk were most likely to be harmed (highest risk decile: posterior probability of OR <1, 87%). In effect-based analysis, a subset of patients identified at high risk of harm (P = .05 for difference in treatment effect) tended to have high BMI and were more likely to require organ support at baseline. Conclusions and Relevance: Among patients hospitalized for COVID-19, the effect of therapeutic-dose heparin was heterogeneous. In all 3 approaches to assessing HTE, heparin was more likely to be beneficial in those who were less severely ill at presentation or had lower BMI and more likely to be harmful in sicker patients and those with higher BMI. The findings illustrate the importance of considering HTE in the design and analysis of RCTs. Trial Registration: ClinicalTrials.gov Identifiers: NCT02735707, NCT04505774, NCT04359277, NCT04372589.

Variation in Clinical Treatment and Outcomes by Race Among US Veterans Hospitalized With COVID-19.

Importance: Patients from racially and ethnically minoritized populations, such as Black and Hispanic patients, may be less likely to receive evidence-based COVID-19 treatments than White patients, contributing to adverse clinical outcomes. Objective: To determine whether clinical treatments and outcomes among patients hospitalized with COVID-19 were associated with race. Design, Setting, and Participants: This retrospective cohort study was conducted in 130 Department of Veterans Affairs Medical Centers (VAMCs) between March 1, 2020, and February 28, 2022, with a 60-day follow-up period until May 1, 2022. Participants included veterans hospitalized with COVID-19. Data were analyzed from May 6 to June 2, 2022. Exposures: Self-reported race. Main Outcomes and Measures: Clinical care processes (eg, intensive care unit [ICU] admission; organ support measures, including invasive and noninvasive mechanical ventilation; prone position therapy, and COVID-19-specific medical treatments) were quantified. Clinical outcomes of interest included in-hospital mortality, 60-day mortality, and 30-day readmissions. Outcomes were assessed with multivariable random effects logistic regression models to estimate the association of race with outcomes not attributable to known mediators, such as socioeconomic status and age, while adjusting for potential confounding between outcomes and mediators. Results: A total of 43 222 veterans (12 135 Black veterans [28.1%]; 31 087 White veterans [71.9%]; 40 717 [94.2%] men) with a median (IQR) age of 71 (62-77) years who were hospitalized with SARS-CoV-2 infection were included. Controlling for site of treatment, Black patients were equally likely to be admitted to the ICU (4806 Black patients [39.6%] vs 13 427 White patients [43.2%]; within-center adjusted odds ratio [aOR], 0.95; 95% CI, 0.88-1.02; P = .17). Two-thirds of patients treated with supplemental oxygen or noninvasive or invasive mechanical ventilation also received systemic steroids, but Black veterans were less likely to receive steroids (within-center aOR, 0.88; 95% CI, 0.80-0.96; P = .004; between-center aOR, 0.67; 95% CI, 0.48-0.96; P = .03). Similarly, Black patients were less likely to receive remdesivir (within-center aOR, 0.89; 95% CI, 0.83-0.95; P < .001; between-center aOR, 0.68; 95% CI, 0.47-0.99; P = .02) or treatment with immunomodulatory drugs (within-center aOR, 0.77; 95% CI, 0.67-0.87; P < .001). After adjusting for patient demographic characteristics, chronic health conditions, severity of acute illness, and receipt of COVID-19-specific treatments, there was no association of Black race with hospital mortality (within-center aOR, 0.98; 95% CI, 0.86-1.10; P = .71) or 30-day readmission (within-center aOR, 0.95; 95% CI, 0.88-1.04; P = .28). Conclusions and Relevance: These findings suggest that Black veterans hospitalized with COVID-19 were less likely to be treated with evidence-based COVID-19 treatments, including systemic steroids, remdesivir, and immunomodulatory drugs.

Comparative COVID-19 Vaccine Effectiveness Over Time in Veterans.

Background: Comparative effectiveness of coronavirus disease 2019 (COVID-19) vaccines across patient subgroups is poorly understood and essential to precisely targeting vaccination strategies. Methods: We used the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify veterans who utilize VA health care and had no documented severe acute respiratory syndrome coronavirus 2 infection before December 11, 2020. Using a test-negative case-control design (TND), we used conditional logistic regression with adjustment for covariates to estimate vaccine effectiveness (VE) over time for veterans who received 2 doses of mRNA vaccines or 1 dose of Ad26.Cov2.S. Results: We identified 4.8 million veterans with a mean age of 64 years, of whom 58% had ≥1 chronic disease. Vaccine effectiveness for symptomatic infections, hospitalizations, and ICU admission or death declined over time and varied by the type of vaccine (P < 0.01). VE estimates against symptomatic infection during months 1 and 7 for mRNA-1273 compared with BNT162b2 were 89.7% (95% CI, 84.4%-93.0%) and 57.3% (95% CI, 48.4%-64.7%) vs 81.6% (95% CI, 75.9%-85.9%) and 22.5% (95% CI, 7.2%-35.2%) for individuals age <65 years and 78.4% (95% CI, 71.1%-83.9%) and 36.2% (95% CI, 27.7%-43.6%) vs 66.3% (95% CI, 55.7%-74.4%) and -23.3% (95% CI, -40.5% to -8.2%) in subjects age ≥65 years; against hospitalization 92.0% (95% CI, 76.1%-97.3%) and 83.1% (95% CI, 66.8%-91.4%) vs 85.6% (95% CI, 72.6%-92.4%) and 57.0% (95% CI, 31.2%-73.2%) in subjects age <65 years and 66.1% (95% CI, 45.3%-79.0%) and 64.7% (95% CI, 55.2%-72.3%) vs 61.0% (95% CI, 41.3%-74.2%) and 1.7% (95% CI, -22.0% to 20.8%) in those age ≥65 years; against ICU admission or death 89.2% (95% CI, 49.5%-97.7%) and 84.4% (95% CI, 59.0%-94.1%) vs 87.6% (95% CI, 61.0%-96.1%) and 66.4% (95% CI, 7.7%-87.8%) in subjects age <65 years and 75.4% (95% CI, 51.7%-87.5%) and 73.8 (95% CI, 62.9%-81.5%) vs 67.4% (95% CI, 32.6%-84.3%) and 29.3% (95% CI, 2.3%-48.9%) in subjects age ≥65 years, respectively (P interaction < .01 for all comparisons). Similarly, mRNA-1273 was more effective than BNT162b2 in veterans with >1 chronic disease. Conclusions: mRNA-1273 was more effective than BNT162b2 in older veterans and those with chronic diseases.

COVID-19 disease severity in US Veterans infected during Omicron and Delta variant predominant periods.

The SARS-CoV-2 Omicron variant is thought to cause less severe disease among the general population, but disease severity among at-risk populations is unknown. We performed a retrospective analysis using a matched cohort of United States veterans to compare the disease severity of subjects infected during Omicron and Delta predominant periods within 14 days of initial diagnosis. We identified 22,841 matched pairs for both periods. During the Omicron period, 20,681 (90.5%) veterans had mild, 1308 (5.7%) moderate, and 852 (3.7%) severe disease. During the Delta predominant period, 19,356 (84.7%) had mild, 1467 (6.4%) moderate, and 2018 (8.8%) severe disease. Moderate or severe disease was less likely during the Omicron period and more common among older subjects and those with more comorbidities. Here we show that infection with the Omicron variant is associated with less severe disease than the Delta variant in a high-risk older veteran population, and vaccinations provide protection against severe or critical disease.

Relative Vaccine Effectiveness of a Severe Acute Respiratory Syndrome Coronavirus 2 Messenger RNA Vaccine Booster Dose Against the Omicron Variant.

BACKGROUND: The current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines may be less effective against the Omicron variant than against earlier variants. With recent resurgence of SARS-CoV-2 cases, the role of booster doses of the vaccine needs to be highlighted. METHODS: Using a retrospective cohort study design emulating a target trial, we determined the relative vaccine effectiveness (RVE) of a homologous booster dose of a SARS-CoV-2 messenger RNA (mRNA) vaccine compared with the primary vaccine series alone in preventing infection, hospitalization, and intensive care unit admission, and death in the Department of Veterans Affairs healthcare system in the United States. Among infection-free survivors who received 2 doses of a mRNA vaccine before 30 April 2021, we identified those who received a booster between 22 September and 25 December 2021 and matched them 1:1 with individuals who did not receive a booster. RESULTS: Among 2 384 272 previously uninfected persons with 2 doses of an mRNA vaccine by 30 April 2021, we identified 462 950 booster recipients between 22 September and 25 December 2021, who were matched 1:1 with non-booster recipients. The RVE (95% confidence interval) was 19% (17%-22%) for confirmed infection, 52% (46%-57%) for hospitalization, and 83% (65%-92%) for intensive care unit admission or death. Recipients of the mRNA-1273 vaccine had a lower cumulative incidence of infections and hospitalizations than recipients of the BNT162b2 vaccine (log-rank P <.001 for both comparisons). CONCLUSIONS: While the RVE of SARS-CoV-2 mRNA booster vaccine dose in preventing infection against the Omicron variant is low, it is substantial in preventing hospitalization and high in preventing the most severe/critical disease.

Vaccine Effectiveness of 3 Versus 2 Doses of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA Vaccines in a High-Risk National Population.

BACKGROUND: Knowledge of the vaccine effectiveness (VE) of a third or booster vaccine dose in preventing SARS-CoV-2 infection or its consequences is critical in developing recommendations for their use. We determined relative VE of 3 vs 2 doses of an mRNA vaccine in preventing symptomatic SARS-CoV-2 infection, hospitalization, and severe/critical disease. METHODS: Among veterans who had received 2 doses of an mRNA vaccine by 30 April 2021, we identified those who received a third dose of the same vaccine between 22 September and 24 November 2021 and 1:1 matched controls who had not received their third dose by then. Using Cox proportional hazards model, we calculated adjusted hazards ratios for symptomatic infection, hospitalization, and intensive care unit (ICU) admission or death after SARS-CoV-2-positive test. RESULTS: Among 2 321 366 veterans who received 2 doses of Pfizer BNT-162b2 or Moderna mRNA-1273 vaccine by 30 April 2021, we matched 395 686 persons who received a third dose of the same vaccine between 22 September and 24 November 2021 to controls who did not receive a third dose. Adjusted HRs (95% CI) were .15 (.11-.21) for symptomatic infection and .18 (.13-.26) for hospitalizations for 3 vs 2 doses, corresponding to relative VE of 85% and 82%. Five ICU admissions or deaths were observed (4 among recipients of 2 doses). There was no difference in VE between BNT162b2 versus mRNA-1273 recipients. CONCLUSIONS: A third dose of a SARS-CoV-2 mRNA vaccine is associated with high VE against symptomatic infection, hospitalization, and critical disease in the pre-Omicron era.

Real-World Effectiveness of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA Vaccines in Preventing Confirmed Infection in Patients on Chronic Hemodialysis.

BACKGROUND: Persons on chronic hemodialysis have a significantly diminished humoral immune response to SARS-CoV-2 vaccines. Whether this translates to reduced vaccine effectiveness (VE) is unknown. METHODS: We used the US Department of Veterans Affairs COVID-19 Shared Data Resource to identify all veterans who were tested for SARS-CoV-2 between 26 January and 31 August 2021. Using International Classification of Diseases, 10th edition, codes and attendance at a dialysis clinic/center, we identified those who were on chronic hemodialysis. We used a test-negative, case-control design using a doubly robust logistic regression model to determine the VE of the BNT-162b2 (Pfizer) or mRNA-1273 (Moderna) vaccines in preventing confirmed SARS-CoV-2 infection. RESULTS: Among 847 199 veterans tested for SARS-CoV-2 between 26 January and 31 August 2021, there were 6076 veterans on chronic hemodialysis. Among those, we identified 1270 cases (580 fully vaccinated) and 2959 controls (2120 fully vaccinated). The overall VE >14 days after the second dose in preventing documented infection was 68.2% (95% CI: 62.6-72.9%). VE was 68.9% (95% CI: 61.9-74.7%) for Pfizer BNT-162b2 and 66.7% (95% CI: 58.9-73.0%) for Moderna mRNA-1273 vaccine. There was no difference in VE by age (<70 vs >70 years), race, or sex. There were no events recorded in persons with a Charlson's comorbidity index score <2. CONCLUSIONS: VE of 2 doses of current mRNA vaccines in preventing SARS-CoV-2 infection in persons on chronic hemodialysis is lower than historic VE rates in the general population. Effects of additional doses in improving VE in this special population need further study.

The Epidemiology of Extremity Threat and Amputation after Vasopressor-Dependent Sepsis.

Rationale: Extremity threat and amputation after sepsis is a well-publicized and devastating event. However, there is a paucity of data about the epidemiology of extremity threat after sepsis onset. Objectives: To estimate the incidence of extremity threat with or without surgical amputation in community sepsis. Methods: Retrospective cohort study of adults with Sepsis-3 hospitalized at 14 academic and community sites from 2013 to 2017. Vasopressor-dependent sepsis was identified by administration of epinephrine, norepinephrine, phenylephrine, vasopressin, or dopamine for more than 1 hour during the 48 hours before to 24 hours after sepsis onset. Outcomes included the incidence of extremity threat, defined as acute onset ischemia, with or without amputation, in the 90 days after sepsis onset. The association between extremity threat, demographics, comorbid conditions, and time-varying sepsis treatments was evaluated using a Cox proportional hazards model. Results: Among 24,365 adults with sepsis, 12,060 (54%) were vasopressor dependent (mean ± standard deviation age, 64 ± 16 years; male, 6,548 [54%]; sequential organ failure assessment [SOFA], 10 ± 4). Of these, 231 (2%) patients had a threatened extremity with 26 undergoing 37 amputations, a risk of 2.2 (95% confidence interval [CI], 1.4-3.2) per 1,000, and 205 not undergoing amputation, a risk of 17.0 (95% CI, 14.8-19.5) per 1,000. Most amputations occurred in lower extremities (95%), a median (interquartile range) of 16 (6-40) days after sepsis onset. Compared with patients with no extremity threat, patients with threat had a higher SOFA score (11 ± 4 vs. 10 ± 4; P < 0.001), serum lactate (4.6 mmol/L [2.4-8.7] vs. 3.1 [1.7-6.0]; P < 0.001), and more bacteremia (n = 37 [37%] vs. n = 2,087 [26%]; P < 0.001) at sepsis onset. Peripheral vascular disease, congestive heart failure, SOFA score, and norepinephrine equivalents were significantly associated with extremity threat. Conclusions: The evaluation of a threatened extremity resulting in surgical amputation occurred in 2 per 1,000 patients with vasopressor-dependent sepsis.

Learning and confirming a class of treatment responders in clinical trials.

Clinical trials require substantial effort and time to complete, and regulatory agencies may require two successful efficacy trials before approving a new drug. One way to improve the chance of follow-up success is to identify a subpopulation among whom treatment effects are estimated to be beneficial, and enrolling future studies from this subpopulation. In this article we study confirmable responder class (CRC) learning, where the objective is to learn in a random half of the dataset (training set) a subpopulation among whom the predicted conditional ATE (CATE) suggests clinically meaningful benefit, with maximum power of being confirmed via hypothesis test in the other half (test set). We studied a set of CRC learners across simulated datasets in which either all patients benefited, or only some did. Performance metrics included the rate of confirmation in the test set, and the classification accuracy of the CRC compared with the group with true CATE>0. In trials where all patients benefitted, only two learners were able to consistently identify most of the population as the CRC. One of these also performed especially well when only some patients benefitted, having relatively high confirmation rates, and showing robustness to the dimension of the covariate vector and population characteristics. This learner is based on cross-validation, and is a possible avenue for further development of model selection criteria for CRC learning. We also show that the performance of all methods can be improved by using both halves of the original dataset as training and test sets in turn.

Sepsis Subclasses: A Framework for Development and Interpretation.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening acute organ dysfunction. It afflicts approximately 50 million people worldwide annually and is often deadly, even when evidence-based guidelines are applied promptly. Many randomized trials tested therapies for sepsis over the past 2 decades, but most have not proven beneficial. This may be because sepsis is a heterogeneous syndrome, characterized by a vast set of clinical and biologic features. Combinations of these features, however, may identify previously unrecognized groups, or "subclasses" with different risks of outcome and response to a given treatment. As efforts to identify sepsis subclasses become more common, many unanswered questions and challenges arise. These include: 1) the semantic underpinning of sepsis subclasses, 2) the conceptual goal of subclasses, 3) considerations about study design, data sources, and statistical methods, 4) the role of emerging data types, and 5) how to determine whether subclasses represent "truth." We discuss these challenges and present a framework for the broader study of sepsis subclasses. This framework is intended to aid in the understanding and interpretation of sepsis subclasses, provide a mechanism for explaining subclasses generated by different methodologic approaches, and guide clinicians in how to consider subclasses in bedside care.

Estimating the Impact of Necrotizing Soft Tissue Infections in the United States: Incidence and Re-Admissions.

Background: Previous estimates of the incidence of necrotizing soft tissue infections (NSTI) in the United States have substantial limitations and underestimate its occurrence. Improvements in hospital mortality after NSTI have increased the number of survivors at risk for long-term sequelae. This study estimates the incidence of NSTI and the burden of re-admission and associated healthcare spending in patients who survived admission for NSTI. Methods: Index admissions for NSTI were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes combined with either Current Procedural Technology (CPT) or diagnosis-related group codes to increase specificity. Two separate datasets were used to provide primary and secondary estimates of the annual incidence of NSTIs in the United States: the National Inpatient Sample (NIS) for the years 2012-2016 and the Watson Health dataset for 2009-2013, respectively, and extrapolated to estimate the incidence for 2018. The Nationwide Readmissions Database (NRD) from 2013-2015 was used to estimate of the risk for re-admission, cost of re-admissions, and to compare 90-day re-admission rates for NSTI to common medical conditions. Results: National Inpatient Sample and Watson Health datasets demonstrated an increasing annual incidence and estimated 33,600 and 28,500 cases in 2018, respectively. The estimated annual incidences in the United States in 2018 were 10.3 and 8.7 per 100,000 persons, respectively. Risk of 90-day re-admission ranged from 24%-29% over the 3 years, 89% of which were unplanned. Of those re-admitted, 90% had one or more comorbidities, the most common diagnoses associated with re-admission were infection in 65%, acute kidney injury in 22%, and shock in 10%. The median re-admission length of stay was seven days (interquartile range [IQR]: 4-13 days) with a median cost of re-admission of $13,590 (IQR: $7186-$27440). Conclusion: The incidence of NSTI is more common than generally reported. Re-admission within 90 days is common, occurring in more than one in four survivors resulting in high healthcare costs.

Bacterial and Fungal Etiology of Sepsis in Children in the United States: Reconsidering Empiric Therapy.

OBJECTIVES: Timely empiric antimicrobial therapy is associated with improved outcomes in pediatric sepsis, but minimal data exist to guide empiric therapy. We sought to describe the prevalence of four pathogens that are not part of routine empiric coverage (e.g., Staphylococcus aureus, Pseudomonas aeruginosa, Clostridium difficile, and fungal infections) in pediatric sepsis patients in a contemporary nationally representative sample. DESIGN: This was a retrospective cohort study using administrative data. SETTING: We used the Nationwide Readmissions Database from 2014, which is a nationally representative dataset that contains data from nearly half of all discharges from nonfederal hospitals in the United States. PATIENTS: Discharges of patients who were less than 19 years old at discharge and were not neonatal with a discharge diagnosis of sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of the 19,113 pediatric admissions with sepsis (6,300 [33%] previously healthy and 12,813 [67%] with a chronic disease), 31% received mechanical ventilation, 19% had shock, and 588 (3.1%) died during their hospitalization. Among all admissions, 8,204 (42.9%) had a bacterial or fungal pathogen identified. S. aureus was the most common pathogen identified in previously healthy patients (n = 593, 9.4%) and those with any chronic disease (n = 1,430, 11.1%). Methicillin-resistant S. aureus, P. aeruginosa, C. difficile, and fungal infections all had high prevalence in specific chronic diseases associated with frequent contact with the healthcare system, early surgery, indwelling devices, or immunosuppression. CONCLUSIONS: In this nationally representative administrative database, the most common identified pathogen was S. aureus in previously healthy and chronically ill children. In addition, a high proportion of children with sepsis and select chronic diseases had infections with methicillin-resistant S. aureus, fungal infections, Pseudomonas infections, and C. difficile. Clinicians caring for pediatric patients should consider coverage of these organisms when administering empiric antimicrobials for sepsis.

Long-term Host Immune Response Trajectories Among Hospitalized Patients With Sepsis.

Importance: Long-term immune sequelae after sepsis are poorly understood. Objective: To assess whether abnormalities in the host immune response during hospitalization for sepsis persist after discharge. Design, Settings, and Participants: This prospective, multicenter cohort study enrolled and followed up for 1 year adults who survived a hospitalization for sepsis from January 10, 2012, to May 25, 2017, at 12 US hospitals. Exposures: Circulating levels of inflammation (interleukin 6 and high-sensitivity C-reactive protein [hs-CRP]), immunosuppression (soluble programmed death ligand 1 [sPD-L1]), hemostasis (plasminogen activator inhibitor 1 and D-dimer), endothelial dysfunction (E-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1), and oxidative stress biomarkers were measured at 5 time points during and after hospitalization for sepsis for 1 year. Individual biomarker trajectories and patterns of trajectories across biomarkers (phenotypes) were identified. Main Outcomes and Measures: Outcomes were adjudicated centrally and included all-cause and cause-specific readmissions and mortality. Results: A total of 483 patients (mean [SD] age, 60.5 [15.2] years; 265 [54.9%] male) who survived hospitalization for sepsis were included in the study. A total of 376 patients (77.8%) had at least 1 chronic disease, and their mean (SD) Sequential Organ Failure Assessment score was 4.2 (3.0). Readmissions were common (485 readmissions in 205 patients [42.5%]), and 43 patients (8.9%) died by 3 months, 56 patients (11.6%) died by 6 months, and 85 patients (17.6%) died by 12 months. Elevated hs-CRP levels were observed in 23 patients (25.8%) at 3 months, 26 patients (30.2%) at 6 months, and 23 patients (25.6%) at 12 months, and elevated sPD-L1 levels were observed in 45 patients (46.4%) at 3 months, 40 patients (44.9%) at 6 months, and 44 patients (49.4%) at 12 months. Two common phenotypes were identified based on hs-CRP and sPDL1 trajectories: high hs-CRP and sPDL1 levels (hyperinflammation and immunosuppression phenotype [326 of 477 (68.3%)]) and normal hs-CRP and sPDL1 levels (normal phenotype [143 of 477 (30.0%)]). These phenotypes had similar clinical characteristics and clinical course during hospitalization for sepsis. Compared with normal phenotype, those with the hyperinflammation and immunosuppression phenotype had higher 1-year mortality (odds ratio, 8.26; 95% CI, 3.45-21.69; P < .001), 6-month all-cause readmission or mortality (hazard ratio [HR], 1.53; 95% CI, 1.10-2.13; P = .01), and 6-month readmission or mortality attributable to cardiovascular disease (HR, 5.07; 95% CI, 1.18-21.84; P = .02) or cancer (HR, 5.15; 95% CI, 1.25-21.18; P = .02). These associations were adjusted for demographic characteristics, chronic diseases, illness severity, organ support, and infection site during sepsis hospitalization and were robust in sensitivity analyses. Conclusions and Relevance: In this study, persistent elevation of inflammation and immunosuppression biomarkers occurred in two-thirds of patients who survived a hospitalization for sepsis and was associated with worse long-term outcomes.

Derivation, Validation, and Potential Treatment Implications of Novel Clinical Phenotypes for Sepsis.

Importance: Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care. Objective: To derive sepsis phenotypes from clinical data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship with results from randomized clinical trials (RCTs). Design, Settings, and Participants: Retrospective analysis of data sets using statistical, machine learning, and simulation tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients) who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania hospitals (2010-2012) using consensus k means clustering applied to 29 variables. Reproducibility and correlation with biological parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086 total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737). Exposures: All clinical and laboratory variables in the electronic health record. Main Outcomes and Measures: Derived phenotype (α, ß, γ, and δ) frequency, host-response biomarkers, 28-day and 365-day mortality, and RCT simulation outputs. Results: The derivation cohort included 20 189 patients with sepsis (mean age, 64 [SD, 17] years; 10 022 [50%] male; mean maximum 24-hour Sequential Organ Failure Assessment [SOFA] score, 3.9 [SD, 2.4]). The validation cohort included 43 086 patients (mean age, 67 [SD, 17] years; 21 993 [51%] male; mean maximum 24-hour SOFA score, 3.6 [SD, 2.0]). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625; 33%) and included patients with the lowest administration of a vasopressor; in the ß phenotype (n = 5512; 27%), patients were older and had more chronic illness and renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more liver dysfunction and septic shock. Phenotype distributions were similar in the validation cohort. There were consistent differences in biomarker patterns by phenotype. In the derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients (5%) for the α phenotype; 561 of 4420 (13%) for the ß phenotype; 1031 of 4318 (24%) for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the other 3 phenotypes (P < .001). In simulation models, the proportion of RCTs reporting benefit, harm, or no effect changed considerably (eg, varying the phenotype frequencies within an RCT of early goal-directed therapy changed the results from >33% chance of benefit to >60% chance of harm). Conclusions and Relevance: In this retrospective analysis of data sets from patients with sepsis, 4 clinical phenotypes were identified that correlated with host-response patterns and clinical outcomes, and simulations suggested these phenotypes may help in understanding heterogeneity of treatment effects. Further research is needed to determine the utility of these phenotypes in clinical care and for informing trial design and interpretation.

Epidemiology of Readmissions After Sepsis Hospitalization in Children.

BACKGROUND AND OBJECTIVES: The decline in hospital mortality in children hospitalized with sepsis has increased the number of survivors. These survivors are at risk for adverse long-term outcomes, including readmission and recurrent or unresolved infections. We described the epidemiology of 90-day readmissions after sepsis hospitalization in children. We tested the hypothesis that a sepsis hospitalization increases odds of 90-day readmissions. METHODS: Retrospective cohort analysis of the Nationwide Readmissions Database. We included index unplanned admissions of non-neonatal pediatric patients and described the proportion of readmissions, including those involving infection or sepsis. We performed multivariable analysis to determine the odds of readmission after a sepsis and nonsepsis admission and compared costs of readmission after sepsis and nonsepsis admissions. RESULTS: Of 562 817 pediatric admissions, 7634 (1.4%) and 555 183 (98.6%) were discharged alive after admissions with and without sepsis. The rate of 90-day readmission after sepsis was 21.4%: 7.2% and 25.5% in previously healthy and chronically ill patients. The adjusted mean cost during readmission was $7385. Half of readmissions (52.9%) involved recurrent infection or sepsis. Sepsis admissions were associated with higher odds of readmission at 90 days compared with nonsepsis admissions (adjusted odds ratio 1.15, 95% confidence interval 1.08-1.23). The results remained unchanged for 30-day and 6-month readmissions. CONCLUSIONS: Readmissions occur after 1 in 5 pediatric sepsis hospitalizations and increase health care costs. Sepsis hospitalization increased odds of readmission and commonly involved recurrent infection or sepsis. Clinicians caring for these patients should consider surveillance for recurrent or unresolved infection, and researchers should explore underlying mechanisms and potential interventions to reduce readmissions.