Clinical Phenotypes of Sepsis in a Cohort of Hospitalized Patients According to Infection Site.

OBJECTIVES: Clinical sepsis phenotypes may be defined by a wide range of characteristics such as site of infection, organ dysfunction patterns, laboratory values, and demographics. There is a paucity of literature regarding the impact of site of infection on the timing and pattern of clinical sepsis markers. This study hypothesizes that important phenotypic variation in clinical markers and outcomes of sepsis exists when stratified by infection site. DESIGN: Retrospective cohort study. SETTING: Five hospitals within the Wake Forest Health System from June 2019 to December 2019. PATIENTS: Six thousand seven hundred fifty-three hospitalized adults with a discharge International Classification of Diseases, 10th Revision code for acute infection who met systemic inflammatory response syndrome (SIRS), quick Sepsis-related Organ Failure Assessment (qSOFA), or Sequential Organ Failure Assessment (SOFA) criteria during the index hospitalization. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome of interest was a composite of 30-day mortality or shock. Infection site was determined by a two-reviewer process. Significant demographic, vital sign, and laboratory result differences were seen across all infection sites. For the composite outcome of shock or 30-day mortality, unknown or unspecified infections had the highest proportion (21.34%) and CNS infections had the lowest proportion (8.11%). Respiratory, vascular, and unknown or unspecified infection sites showed a significantly increased adjusted and unadjusted odds of the composite outcome as compared with the other infection sites except CNS. Hospital time prior to SIRS positivity was shortest in unknown or unspecified infections at a median of 0.88 hours (interquartile range [IQR], 0.22-5.05 hr), and hospital time prior to qSOFA and SOFA positivity was shortest in respiratory infections at a median of 54.83 hours (IQR, 9.55-104.67 hr) and 1.88 hours (IQR, 0.47-17.40 hr), respectively. CONCLUSIONS: Phenotypic variation in illness severity and mortality exists when stratified by infection site. There is a significantly higher adjusted and unadjusted odds of the composite outcome of 30-day mortality or shock in respiratory, vascular, and unknown or unspecified infections as compared with other sites.

Sepsis Prediction Model for Determining Sepsis vs SIRS, qSOFA, and SOFA.

Importance: The Sepsis Prediction Model (SPM) is a proprietary decision support tool created by Epic Systems; it generates a predicting sepsis score (PSS). The model has not undergone validation against existing sepsis prediction tools, such as Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), or quick Sepsis-Related Organ Failure Asessement (qSOFA). Objective: To assess the validity and timeliness of the SPM compared with SIRS, qSOFA, and SOFA. Design, Setting, and Participants: This retrospective cohort study included all adults admitted to 5 acute care hospitals in a single US health system between June 5, 2019, and December 31, 2020. Data analysis was conducted from March 2021 to February 2023. Main Outcomes and Measures: A sepsis event was defined as receipt of 4 or more days of antimicrobials, blood cultures collected within ±48 hours of initial antimicrobial, and at least 1 organ dysfunction as defined by the organ dysfunction criteria optimized for the electronic health record (eSOFA). Time zero was defined as 15 minutes prior to qualifying antimicrobial or blood culture order. Results: Of 60 507 total admissions, 1663 (2.7%) met sepsis criteria, with 1324 electronic health record-confirmed sepsis (699 [52.8%] male patients; 298 [22.5%] Black patients; 46 [3.5%] Hispanic/Latinx patients; 945 [71.4%] White patients), 339 COVID-19 sepsis (183 [54.0%] male patients; 98 [28.9%] Black patients; 36 [10.6%] Hispanic/Latinx patients; and 189 [55.8%] White patients), and 58 844 (97.3%; 26 632 [45.2%] male patients; 12 698 [21.6%] Black patients; 3367 [5.7%] Hispanic/Latinx patients; 40 491 White patients) did not meet sepsis criteria. The median (IQR) age was 63 (51 to 73) years for electronic health record-confirmed sepsis, 69 (60 to 77) years for COVID-19 sepsis, and 60 (42 to 72) years for nonsepsis admissions. Within the vendor recommended threshold PSS range of 5 to 8, PSS of 8 or greater had the highest balanced accuracy for classifying a sepsis admission at 0.79 (95% CI, 0.78 to 0.80). Change in SOFA score of 2 or more had the highest sensitivity, at 0.97 (95% CI, 0.97 to 0.98). At a PSS of 8 or greater, median (IQR) time to score positivity from time zero was 68.00 (6.75 to 605.75) minutes. For SIRS, qSOFA, and SOFA, median (IQR) time to score positivity was 7.00 (-105.00 to 08.00) minutes, 74.00 (-22.25 to 599.25) minutes, and 28.00 (-108.50 to 134.00) minutes, respectively. Conclusions and Relevance: In this cohort study of hospital admissions, balanced accuracy of the SPM outperformed other models at higher threshold PSS; however, application of the SPM in a clinical setting was limited by poor timeliness as a sepsis screening tool as compared to SIRS and SOFA.

Clinical Impact of a Sepsis Alert System Plus Electronic Sepsis Navigator Using the Epic Sepsis Prediction Model in the Emergency Department.

BACKGROUND: The Epic Sepsis Prediction Model (SPM) is a proprietary sepsis prediction algorithm that calculates a score correlating with the likelihood of an International Classification of Diseases, Ninth Revision code for sepsis. OBJECTIVE: This study aimed to assess the clinical impact of an electronic sepsis alert and navigator using the Epic SPM on time to initial antimicrobial delivery. METHODS: We performed a retrospective review of a nonrandomized intervention of an electronic sepsis alert system and navigator using the Epic SPM. Data from the SPM site (site A) was compared with contemporaneous data from hospitals within the same health care system (sites B-D) and historical data from site A. Nonintervention sites used a systemic inflammatory response syndrome (SIRS)-based alert without a sepsis navigator. RESULTS: A total of 5368 admissions met inclusion criteria. Time to initial antimicrobial delivery from emergency department arrival was 3.33 h (interquartile range [IQR] 2.10-5.37 h) at site A, 3.22 h (IQR 1.97-5.60; p = 0.437, reference site A) at sites B-D, and 6.20 h (IQR 3.49-11.61 h; p < 0.001, reference site A) at site A historical. After adjustment using matching weights, there was no difference in time from threshold SPM score to initial antimicrobial between contemporaneous sites. Adjusted time to initial antimicrobial improved by 2.87 h (p < 0.001) at site A compared with site A historical. CONCLUSIONS: Implementation of an electronic sepsis alert system plus navigator using the Epic SPM showed no difference in time to initial antimicrobial delivery between the contemporaneous SPM alert plus sepsis navigator site and the SIRS-based electronic alert sites within the same health care system.

I-SPY COVID adaptive platform trial for COVID-19 acute respiratory failure: rationale, design and operations.

INTRODUCTION: The COVID-19 pandemic brought an urgent need to discover novel effective therapeutics for patients hospitalised with severe COVID-19. The Investigation of Serial studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis (ISPY COVID-19 trial) was designed and implemented in early 2020 to evaluate investigational agents rapidly and simultaneously on a phase 2 adaptive platform. This manuscript outlines the design, rationale, implementation and challenges of the ISPY COVID-19 trial during the first phase of trial activity from April 2020 until December 2021. METHODS AND ANALYSIS: The ISPY COVID-19 Trial is a multicentre open-label phase 2 platform trial in the USA designed to evaluate therapeutics that may have a large effect on improving outcomes from severe COVID-19. The ISPY COVID-19 Trial network includes academic and community hospitals with significant geographical diversity across the country. Enrolled patients are randomised to receive one of up to four investigational agents or a control and are evaluated for a family of two primary outcomes-time to recovery and mortality. The statistical design uses a Bayesian model with 'stopping' and 'graduation' criteria designed to efficiently discard ineffective therapies and graduate promising agents for definitive efficacy trials. Each investigational agent arm enrols to a maximum of 125 patients per arm and is compared with concurrent controls. As of December 2021, 11 investigational agent arms had been activated, and 8 arms were complete. Enrolment and adaptation of the trial design are ongoing. ETHICS AND DISSEMINATION: ISPY COVID-19 operates under a central institutional review board via Wake Forest School of Medicine IRB00066805. Data generated from this trial will be reported in peer-reviewed medical journals. TRIAL REGISTRATION NUMBER: NCT04488081.

Intrapleural nano-immunotherapy promotes innate and adaptive immune responses to enhance anti-PD-L1 therapy for malignant pleural effusion.

Malignant pleural effusion (MPE) is indicative of terminal malignancy with a uniformly fatal prognosis. Often, two distinct compartments of tumour microenvironment, the effusion and disseminated pleural tumours, co-exist in the pleural cavity, presenting a major challenge for therapeutic interventions and drug delivery. Clinical evidence suggests that MPE comprises abundant tumour-associated myeloid cells with the tumour-promoting phenotype, impairing antitumour immunity. Here we developed a liposomal nanoparticle loaded with cyclic dinucleotide (LNP-CDN) for targeted activation of stimulators of interferon genes signalling in macrophages and dendritic cells and showed that, on intrapleural administration, they induce drastic changes in the transcriptional landscape in MPE, mitigating the immune cold MPE in both effusion and pleural tumours. Moreover, combination immunotherapy with blockade of programmed death ligand 1 potently reduced MPE volume and inhibited tumour growth not only in the pleural cavity but also in the lung parenchyma, conferring significantly prolonged survival of MPE-bearing mice. Furthermore, the LNP-CDN-induced immunological effects were also observed with clinical MPE samples, suggesting the potential of intrapleural LNP-CDN for clinical MPE immunotherapy.

Dysregulated Pyrimidine Biosynthesis Contributes to 5-FU Resistance in SCLC Patient-Derived Organoids but Response to a Novel Polymeric Fluoropyrimidine, CF10.

Chemo-immunotherapy is central to the treatment of small cell lung cancer (SCLC). Despite modest progress made with the addition of immunotherapy, current cytotoxic regimens display minimal survival benefit and new treatments are needed. Thymidylate synthase (TS) is a well-validated anti-cancer drug target, but conventional TS inhibitors display limited clinical efficacy in refractory or recurrent SCLC. We performed RNA-Seq analysis to identify gene expression changes in SCLC biopsy samples to provide mechanistic insight into the potential utility of targeting pyrimidine biosynthesis to treat SCLC. We identified systematic dysregulation of pyrimidine biosynthesis, including elevated TYMS expression that likely contributes to the lack of efficacy for current TS inhibitors in SCLC. We also identified E2F1-3 upregulation in SCLC as a potential driver of TYMS expression that may contribute to tumor aggressiveness. To test if TS inhibition could be a viable strategy for SCLC treatment, we developed patient-derived organoids (PDOs) from human SCLC biopsy samples and used these to evaluate both conventional fluoropyrimidine drugs (e.g., 5-fluorouracil), platinum-based drugs, and CF10, a novel fluoropyrimidine polymer with enhanced TS inhibition activity. PDOs were relatively resistant to 5-FU and while moderately sensitive to the front-line agent cisplatin, were relatively more sensitive to CF10. Our studies demonstrate dysregulated pyrimidine biosynthesis contributes to drug resistance in SCLC and indicate that a novel approach to target these pathways may improve outcomes.

Code status orders and goals of care in the medical ICU.

BACKGROUND: Decisions about CPR in the medical ICU (MICU) are important. However, discussions about CPR (code status discussions) can be challenging and may be incomplete if they do not address goals of care. METHODS: We interviewed 100 patients, or their surrogates, and their physicians in an MICU. We queried the patients/surrogates on their knowledge of CPR, code status preferences, and goals of care; we queried MICU physicians about goals of care and treatment plans. Medical records were reviewed for clinical information and code status orders. RESULTS: Fifty patients/surrogates recalled discussing CPR preferences with a physician, and 51 recalled discussing goals of care. Eighty-three patients/surrogates preferred full code status, but only four could identify the three main components of in-hospital CPR (defibrillation, chest compressions, intubation). There were 16 discrepancies between code status preferences expressed during the interview and code status orders in the medical record. Respondents' average prediction of survival following in-hospital cardiac arrest with CPR was 71.8%, and the higher the prediction of survival, the greater the frequency of preference for full code status (P = .012). Of six possible goals of care, approximately five were affirmed by each patient/surrogate and physician, but 67.7% of patients/surrogates differed with their physicians about the most important goal of care. CONCLUSIONS: Patients in the MICU and their surrogates have inadequate knowledge about in-hospital CPR and its likelihood of success, patients' code status preferences may not always be reflected in code status orders, and assessments may differ between patients/surrogates and physicians about what goal of care is most important.

Use of mechanical and noninvasive ventilation in black and white chronic obstructive pulmonary disease patients within the Veterans Administration health care system.

BACKGROUND: Black patients are more likely than white patients to prefer and receive more life-sustaining interventions in advanced stages of disease. However, little is known about potential racial differences in use of mechanical ventilation (MV), and the newer modality of noninvasive ventilation (NIV), in treatment of chronic obstructive pulmonary disease (COPD). OBJECTIVE: To determine if rates of MV and NIV use differ among black and white patients admitted to Veterans Administration (VA) hospitals for COPD exacerbation. RESEARCH DESIGN: Retrospective cohort analysis of VA database FY2003 to FY2005 including 153 hospitals nationwide. SUBJECTS: All black (n = 479) and white (n = 31,537) patients admitted with COPD exacerbation. MEASURES: Ventilation use during hospitalization as identified by ICD-9-CM codes for MV and NIV. Hierarchical logistic regression compared rates of MV or NIV use among black and white patients, adjusting for patient characteristics and accounting for hospital-level variation. RESULTS: Unadjusted rates of MV were higher in black patients than in white patients (4.1% vs. 3.0%; P < 0.001), but similar for NIV (6.0% vs. 6.1%; P = 0.65). The adjusted odds of MV for black patients relative to white patients remained higher (OR = 1.27, 95% CI: 1.01-1.54; P < 0.01) while the adjusted odds of NIV remained similar (OR = 0.94, 95% CI: 0.82-1.08; P = 0.38). CONCLUSIONS: Black patients with COPD exacerbation in VA hospitals are more likely than white patients to receive MV, and this difference is not explained by available clinical or demographic variables. By contrast, black and white patients are equally likely to receive NIV. These findings suggest that unmeasured factors, such as patient preferences or disease severity, may be affecting the use of MV in this setting and therefore warrant further investigation.

Presumed antepartum amniotic fluid embolism.

BACKGROUND: Amniotic fluid embolism is seldom recognized in nonperipartum patients. The pathophysiology is uncertain and diagnosis imprecise, making management after stabilization difficult. CASE: A 37-year-old woman at 28 weeks' gestation presented with signs and symptoms consistent with amniotic fluid embolism including disseminated intravascular coagulopathy. A ventilation-perfusion scan demonstrated unmatched perfusion defects, but other radiographic studies were negative; the patient was treated with heparin. Four days after presentation she had spontaneous rupture of membranes followed by hypoxemia, necessitating cesarean delivery. A pulmonary arteriogram after the operation showed multiple filling defects; the patient was discharged on warfarin. CONCLUSION: Amniotic fluid embolism is a difficult diagnosis to make, at best. Anticoagulation may be a therapeutic option.

Respiratory syncytial virus inhibits apoptosis and induces NF-kappa B activity through a phosphatidylinositol 3-kinase-dependent pathway.

Respiratory syncytial virus (RSV) infects airway epithelial cells, resulting in cell death and severe inflammation through the induction of NF-kappaB activity and inflammatory cytokine synthesis. Both NF-kappaB activity and apoptosis regulation have been linked to phosphatidylinositol 3-kinase (PI 3-K) and its downstream effector enzymes, AKT and GSK-3. This study evaluates the role of PI 3-K and its downstream mediators in apoptosis and inflammatory gene induction during RSV infection of airway epithelial cells. Whereas RSV infection alone did not produce significant cytotoxicity until 24-48 h following infection, simultaneous RSV infection and exposure to LY294002, a blocker of PI 3-K activity, resulted in cytotoxicity within 12 h. Furthermore, we found that RSV infection during PI 3-K blockade resulted in apoptosis by examining DNA fragmentation, DNA labeling by terminal dUTP nick-end labeling assay, and poly(ADP-ribose) polymerase cleavage by Western blotting. RSV infection produced an increase in the phosphorylation state of AKT, GSK-3, and the p85 regulatory subunit of PI 3-K. The activation of PI 3-K by RSV and its inhibition by LY294002 was confirmed in direct PI 3-K activity assays. Further evidence for the central role of a pathway involving PI 3-K and AKT in preserving cell viability during RSV infection was established by the observation that constitutively active AKT transfected into A549 cells prevented the cytotoxicity and apoptosis of combined RSV and LY294002 treatment. Finally, both PI 3-K inhibition by LY294002 and AKT inhibition by transfection of a dominant negative enzyme blocked RSV-induced NF-kappaB transcriptional activity. These data demonstrate that anti-apoptotic signaling and NF-kappaB activation by RSV are mediated through activation of PI 3-K-dependent pathways. Blockade of PI 3-K activation resulted in rapid, premature apoptosis and inhibition of RSV-stimulated NF-kappaB-dependent gene transcription.