ACE inhibitors and angiotensin receptor blockers differentially alter the response to angiotensin II treatment in vasodilatory shock.

BACKGROUND: Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB) medications are widely prescribed. We sought to assess how pre-admission use of these medications might impact the response to angiotensin-II treatment during vasodilatory shock. METHODS: In a post-hoc subgroup analysis of the randomized, placebo-controlled, Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we compared patients with chronic angiotensin-converting enzyme inhibitor (ACEi) use, and patients with angiotensin receptor blocker (ARB) use, to patients without exposure to either ACEi or ARB. The primary outcome was mean arterial pressure after 1-h of treatment. Additional clinical outcomes included mean arterial pressure and norepinephrine equivalent dose requirements over time, and study-drug dose over time. Biological outcomes included baseline RAS biomarkers (renin, angiotensin-I, angiotensin-II, and angiotensin-I/angiotensin-II ratio), and the change in renin from 0 to 3 h. RESULTS: We included n = 321 patients, of whom, 270 were ACEi and ARB-unexposed, 29 were ACEi-exposed and 22 ARB-exposed. In ACEi/ARB-unexposed patients, angiotensin-treated patients, compared to placebo, had higher hour-1 mean arterial pressure (9.1 mmHg [95% CI 7.6-10.1], p < 0.0001), lower norepinephrine equivalent dose over 48-h (p = 0.0037), and lower study-drug dose over 48-h (p < 0.0001). ACEi-exposed patients treated with angiotensin-II showed similarly higher hour-1 mean arterial pressure compared to ACEi/ARB-unexposed (difference in treatment-effect: - 2.2 mmHg [95% CI - 7.0-2.6], pinteraction = 0.38), but a greater reduction in norepinephrine equivalent dose (pinteraction = 0.0031) and study-drug dose (pinteraction < 0.0001) over 48-h. In contrast, ARB-exposed patients showed an attenuated effect of angiotensin-II on hour-1 mean arterial pressure versus ACEi/ARB-unexposed (difference in treatment-effect: - 6.0 mmHg [95% CI - 11.5 to - 0.6], pinteraction = 0.0299), norepinephrine equivalent dose (pinteraction < 0.0001), and study-drug dose (pinteraction = 0.0008). Baseline renin levels and angiotensin-I/angiotensin-II ratios were highest in ACEi-exposed patients. Finally, angiotensin-II treatment reduced hour-3 renin in ACEi/ARB-unexposed and ACEi-exposed patients but not in ARB-exposed patients. CONCLUSIONS: In vasodilatory shock patients, the cardiovascular and biological RAS response to angiotensin-II differed based upon prior exposure to ACEi and ARB medications. ACEi-exposure was associated with increased angiotensin II responsiveness, whereas ARB-exposure was associated with decreased responsiveness. These findings have clinical implications for patient selection and dosage of angiotensin II in vasodilatory shock. Trial Registration ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

SARS-CoV-2 infection elucidates unique features of pregnancy-specific immunity.

Pregnancy is a risk factor for increased severity of SARS-CoV-2 and other respiratory infections. The mechanisms underlying this risk have not been well-established, partly due to a limited understanding of how pregnancy shapes immune responses. To gain insight into the role of pregnancy in modulating immune responses at steady state and upon perturbation, we collected peripheral blood mononuclear cells (PBMC), plasma, and stool from 226 women, including 152 pregnant individuals (n = 96 with SARS-CoV-2 infection and n = 56 healthy controls) and 74 non-pregnant women (n = 55 with SARS-CoV-2 and n = 19 healthy controls). We found that SARS-CoV-2 infection was associated with altered T cell responses in pregnant compared to non-pregnant women. Differences included a lower percentage of memory T cells, a distinct clonal expansion of CD4-expressing CD8 + T cells, and the enhanced expression of T cell exhaustion markers, such as programmed cell death-1 (PD-1) and T cell immunoglobulin and mucin domain-3 (Tim-3), in pregnant women. We identified additional evidence of immune dysfunction in severely and critically ill pregnant women, including a lack of expected elevation in regulatory T cell (Treg) levels, diminished interferon responses, and profound suppression of monocyte function. Consistent with earlier data, we found maternal obesity was also associated with altered immune responses to SARS-CoV-2 infection, including enhanced production of inflammatory cytokines by T cells. Certain gut bacterial species were altered in pregnancy and upon SARS-CoV-2 infection in pregnant individuals compared to non-pregnant women. Shifts in cytokine and chemokine levels were also identified in the sera of pregnant individuals, most notably a robust increase of interleukin-27 (IL-27), a cytokine known to drive T cell exhaustion, in the pregnant uninfected control group compared to all non-pregnant groups. IL-27 levels were also significantly higher in uninfected pregnant controls compared to pregnant SARS-CoV-2-infected individuals. Using two different preclinical mouse models of inflammation-induced fetal demise and respiratory influenza viral infection, we found that enhanced IL-27 protects developing fetuses from maternal inflammation but renders adult female mice vulnerable to viral infection. These combined findings from human and murine studies reveal nuanced pregnancy-associated immune responses, suggesting mechanisms underlying the increased susceptibility of pregnant individuals to viral respiratory infections.

Integrated Immunopeptidomic and Proteomic Analysis of COVID-19 lung biopsies.

Introduction: Severe respiratory illness is the most prominent manifestation of patients infected with SARS-CoV-2, and yet the molecular mechanisms underlying severe lung disease in COVID-19 affected patients still require elucidation. Human leukocyte antigen class I (HLA-I) expression is crucial for antigen presentation and the host's response to SARS-CoV-2. Methods: To gain insights into the immune response and molecular pathways involved in severe lung disease, we performed immunopeptidomic and proteomic analyses of lung tissues recovered at four COVID-19 autopsy and six non-COVID-19 transplants. Results: We found signals of tissue injury and regeneration in lung fibroblast and alveolar type I/II cells, resulting in the production of highly immunogenic self-antigens within the lungs of COVID-19 patients. We also identified immune activation of the M2c macrophage as the primary source of HLA-I presentation and immunogenicity in this context. Additionally, we identified 28 lung signatures that can serve as early plasma markers for predicting infection and severe COVID-19 disease. These protein signatures were predominantly expressed in macrophages and epithelial cells and were associated with complement and coagulation cascades. Discussion: Our findings emphasize the significant role of macrophage-mediated immunity in the development of severe lung disease in COVID-19 patients.

Diagnostic suspicion bias and machine learning: Breaking the awareness deadlock for sepsis detection.

Many early warning algorithms are downstream of clinical evaluation and diagnostic testing, which means that they may not be useful when clinicians fail to suspect illness and fail to order appropriate tests. Depending on how such algorithms handle missing data, they could even indicate "low risk" simply because the testing data were never ordered. We considered predictive methodologies to identify sepsis at triage, before diagnostic tests are ordered, in a busy Emergency Department (ED). One algorithm used "bland clinical data" (data available at triage for nearly every patient). The second algorithm added three yes/no questions to be answered after the triage interview. Retrospectively, we studied adult patients from a single ED between 2014-16, separated into training (70%) and testing (30%) cohorts, and a final validation cohort of patients from four EDs between 2016-2018. Sepsis was defined per the Rhee criteria. Investigational predictors were demographics and triage vital signs (downloaded from the hospital EMR); past medical history; and the auxiliary queries (answered by chart reviewers who were blinded to all data except the triage note and initial HPI). We developed L2-regularized logistic regression models using a greedy forward feature selection. There were 1164, 499, and 784 patients in the training, testing, and validation cohorts, respectively. The bland clinical data model yielded ROC AUC's 0.78 (0.76-0.81) and 0.77 (0.73-0.81), for training and testing, respectively, and ranged from 0.74-0.79 in four hospital validation. The second model which included auxiliary queries yielded 0.84 (0.82-0.87) and 0.83 (0.79-0.86), and ranged from 0.78-0.83 in four hospital validation. The first algorithm did not require clinician input but yielded middling performance. The second showed a trend towards superior performance, though required additional user effort. These methods are alternatives to predictive algorithms downstream of clinical evaluation and diagnostic testing. For hospital early warning algorithms, consideration should be given to bias and usability of various methods.

Risk of Misleading Conclusions in Observational Studies of Time-to-Antibiotics and Mortality in Suspected Sepsis.

BACKGROUND: Influential studies conclude that each hour until antibiotics increases mortality in sepsis. However, these analyses often (1) adjusted for limited covariates, (2) included patients with long delays until antibiotics, (3) combined sepsis and septic shock, and (4) used linear models presuming each hour delay has equal impact. We evaluated the effect of these analytic choices on associations between time-to-antibiotics and mortality. METHODS: We retrospectively identified 104 248 adults admitted to 5 hospitals from 2015-2022 with suspected infection (blood culture collection and intravenous antibiotics ≤24 h of arrival), including 25 990 with suspected septic shock and 23 619 with sepsis without shock. We used multivariable regression to calculate associations between time-to-antibiotics and in-hospital mortality under successively broader confounding-adjustment, shorter maximum time-to-antibiotic intervals, stratification by illness severity, and removing assumptions of linear hourly associations. RESULTS: Changing covariates, maximum time-to-antibiotics, and severity stratification altered the magnitude, direction, and significance of observed associations between time-to-antibiotics and mortality. In a fully adjusted model of patients treated ≤6 hours, each hour was associated with higher mortality for septic shock (adjusted odds ratio [aOR]: 1.07; 95% CI: 1.04-1.11) but not sepsis without shock (aOR: 1.03; .98-1.09) or suspected infection alone (aOR: .99; .94-1.05). Modeling each hour separately confirmed that every hour of delay was associated with increased mortality for septic shock, but only delays >6 hours were associated with higher mortality for sepsis without shock. CONCLUSIONS: Associations between time-to-antibiotics and mortality in sepsis are highly sensitive to analytic choices. Failure to adequately address these issues can generate misleading conclusions.

Can tablet video-based telehealth assessment of the abdomen safely determine the need for abdominal imaging? A pilot study.

Objective: There is limited evidence on the reliability of video-based physical examinations. We aimed to evaluate the safety of a remote physician-directed abdominal examination using tablet-based video. Methods: This was a prospective observational pilot study of patients >19 years old presenting with abdominal pain to an academic emergency department July 9, 2021-December 21, 2021. In addition to usual care, patients had a tablet video-based telehealth history and examination by an emergency physician who was otherwise not involved in the visit. Both telehealth and in-person clinicians were asked about the patient's need for abdominal imaging (yes/no). Thirty-day chart review searched for subsequent ED visits, hospitalizations, and procedures. Our primary outcome was agreement between telehealth and in-person clinicians on imaging need. Our secondary outcome was potentially missed imaging by the telehealth physicians leading to morbidity or mortality. We used descriptive and bivariate analyses to examine characteristics associated with disagreement on imaging needs. Results: Fifty-six patients were enrolled; the median age was 43 years (interquartile range: 27-59), 31 (55%) were female. The telehealth and in-person clinicians agreed on the need for imaging in 42 (75%) of the patients (95% confidence interval [CI]: 62%-86%), with moderate agreement with Cohen's kappa ((k = 0.41, 95% CI: 0.15-0.67). For study patients who had a procedure within 24 hours of ED arrival (n = 3, 5.4%, 95% CI: 1.1%-14.9%) or within 30 days (n = 7, 12.5%, 95% CI: 5.2%-24.1%), neither telehealth physicians nor in-person clinicians missed timely imaging. Conclusion: In this pilot study, telehealth physicians and in-person clinicians agreed on the need for imaging for the majority of patients with abdominal pain. Importantly, telehealth physicians did not miss the identification of imaging needs for patients requiring urgent or emergent surgery.

Association Between Metabolic Syndrome Inflammatory Biomarkers and COVID-19 Severity.

Context: Metabolic syndrome (MetS) is associated with increased risk of severe COVID-19. MetS inflammatory biomarkers share similarities with those of COVID-19, yet this association is poorly explored. Objective: Biomarkers of COVID-19 patients with and without MetS, the combination of diabetes, hypertension, obesity, and/or dyslipidemia, were analyzed to identify biological predictors of COVID-19 severity. Methods: In this prospective observational study, at a large academic emergency department in Boston, Massachusetts, clinical and proteomics data were analyzed from March 24 to April 30, 2020. Patients age ≥18 with a clinical concern for COVID-19 upon arrival and acute respiratory distress were included. The main outcome was severe COVID-19 as defined using World Health Organization COVID-19 outcomes scores ≤4, which describes patients who died, required invasive mechanical ventilation, or required supplemental oxygen. Results: Among 155 COVID-19 patients, 90 (58.1%) met the definition of MetS and 65 (41.9%) were identified as Control. The MetS cohort was more likely to have severe COVID-19 compared with the Control cohort (OR 2.67 [CI 1.09-6.55]). Biomarkers, including CXCL10 (OR 1.94 [CI 1.38-2.73]), CXCL9 (OR 1.79 [CI 1.09-2.93]), HGF (OR 3.30 [CI 1.65-6.58]), and IL6 (OR 2.09 [CI 1.49-2.94]) were associated with severe COVID-19. However, when stratified by MetS, only CXCL10 (OR 2.39 [CI 1.38-4.14]) and IL6 (OR 3.14 [CI 1.53-6.45]) were significantly associated with severe COVID-19. Conclusions: MetS-associated severe COVID-19 is characterized by an immune signature of elevated levels of CXCL10 and IL6. Clinical trials targeting CXCL10 or IL6 antagonism in this population may be warranted.

Distinct subsets of neutrophils crosstalk with cytokines and metabolites in patients with sepsis.

Sepsis is a life-threatening condition caused by a dysregulated host response to infection. Despite continued efforts to understand the pathophysiology of sepsis, no effective therapies are currently available. While singular components of the aberrant immune response have been investigated, comprehensive studies linking different data layers are lacking. Using an integrated systems immunology approach, we evaluated neutrophil phenotypes and concomitant changes in cytokines and metabolites in patients with sepsis. Our findings identify differentially expressed mature and immature neutrophil subsets in patients with sepsis. These subsets correlate with various proteins, metabolites, and lipids, including pentraxin-3, angiopoietin-2, and lysophosphatidylcholines, in patients with sepsis. These results enabled the construction of a statistical model based on weighted multi-omics linear regression analysis for sepsis biomarker identification. These findings could help inform early patient stratification and treatment options, and facilitate further mechanistic studies targeting the trifecta of surface marker expression, cytokines, and metabolites.

Implementation of an Electronic Alert to Improve Timeliness of Second Dose Antibiotics for Patients With Suspected Serious Infections in the Emergency Department: A Quasi-Randomized Controlled Trial.

STUDY OBJECTIVE: Delays in the second dose of antibiotics in the emergency department (ED) are associated with increased morbidity and mortality in patients with serious infections. We analyzed the influence of clinical decision support to prevent delays in second doses of broad-spectrum antibiotics in the ED. METHODS: We allocated adult patients who received cefepime or piperacillin/tazobactam in 9 EDs within an integrated health care system to an electronic alert that reminded ED clinicians to reorder antibiotics at the appropriate interval vs usual care. The primary outcome was a median delay in antibiotic administration. Secondary outcomes were rates of intensive care unit (ICU) admission, hospital mortality, and hospital length of stay. We included a post hoc secondary outcome of frequency of major delay (>25% of expected interval for second antibiotic dose). RESULTS: A total of 1,113 ED patients treated with cefepime or piperacillin/tazobactam were enrolled in the study, of whom 420 remained under ED care when their second dose was due and were included in the final analysis. The clinical decision support tool was associated with reduced antibiotic delays (median difference 35 minutes, 95% confidence interval [CI], 5 to 65). There were no differences in ICU transfers, inpatient mortality, or hospital length of stay. The clinical decision support tool was associated with decreased probability of major delay (absolute risk reduction 13%, 95% CI, 6 to 20). CONCLUSIONS: The implementation of a clinical decision support alert reminding clinicians to reorder second doses of antibiotics was associated with a reduction in the length and frequency of antibiotic delays in the ED. There was no effect on the rates of ICU transfers, inpatient mortality, or hospital length of stay.

Can video-based telehealth examinations of the abdomen safely determine the need for imaging?

There is little evidence on the reliability of the video-based telehealth physical examinations. Our objective was to evaluate the feasibility of a physician-directed abdominal examination using telehealth. This was a prospective, blinded observational study of patients >19 years of age presenting with abdominal pain to a large, academic emergency department. In addition to their usual care, patients had a video-based telehealth examination by an emergency physician early in the visit. We compared the in-person and telehealth providers' decisions on imaging. Thirty patients were enrolled and providers' recommendations for imaging were YES (telehealth: 18 (60%); in-person: 22 (73%)), UNSURE (telehealth: 9 (30%); in-person: 2 (7%)) and NO (telehealth: 6 (20%); in-person: 3 (10%)). There were 20 patients for whom both telehealth and in-person providers were not unsure; of these, 16 (80%, 95% confidence interval 56.3-94.3%) patients had a provider agreement on the need for imaging. While the use of video-based telehealth may be feasible for patients seeking emergency department care for abdominal pain, further study is needed to determine how it may be safely deployed. Currently, caution should be exercised when evaluating the need for abdominal imaging remotely.

Diagnostic Accuracy of a Bacterial and Viral Biomarker Point-of-Care Test in the Outpatient Setting.

Importance: Acute respiratory infections (ARIs) account for most outpatient visits. Discriminating bacterial vs viral etiology is a diagnostic challenge with therapeutic implications. Objective: To investigate whether FebriDx, a rapid, point-of-care immunoassay, can differentiate bacterial- from viral-associated host immune response in ARI through measurement of myxovirus resistance protein A (MxA) and C-reactive protein (CRP) from finger-stick blood. Design, Setting, and Participants: This diagnostic study enrolled adults and children who were symptomatic for ARI and individuals in a control group who were asymptomatic between October 2019 and April 2021. Included participants were a convenience sample of patients in outpatient settings (ie, emergency department, urgent care, and primary care) who were symptomatic, aged 1 year or older, and had suspected ARI and fever within 72 hours. Individuals with immunocompromised state and recent vaccine, antibiotics, stroke, surgery, major burn, or myocardial infarction were excluded. Of 1685 individuals assessed for eligibility, 259 individuals declined participation, 718 individuals were excluded, and 708 individuals were enrolled (520 patients with ARI, 170 patients without ARI, and 18 individuals who dropped out). Exposures: Bacterial and viral immunoassay testing was performed using finger-stick blood. Results were read at 10 minutes, and treating clinicians and adjudicators were blinded to results. Main Outcomes and Measures: Bacterial- or viral-associated systemic host response to an ARI as determined by a predefined comparator algorithm with adjudication classified infection etiology. Results: Among 520 participants with ARI (230 male patients [44.2%] and 290 female patients [55.8%]; mean [SD] age, 35.3 [17.7] years), 24 participants with missing laboratory information were classified as unknown (4.6%). Among 496 participants with a final diagnosis, 73 individuals (14.7%) were classified as having a bacterial-associated response, 296 individuals (59.7%) as having a viral-associated response, and 127 individuals (25.6%) as negative by the reference standard. The bacterial and viral test correctly classified 68 of 73 bacterial infections, demonstrating a sensitivity of 93.2% (95% CI, 84.9%-97.0%), specificity of 374 of 423 participants (88.4% [95% CI, 85.0%-91.1%]), positive predictive value (PPV) of 68 of 117 participants (58.1% [95% CI, 49.1%-66.7%), and negative predictive value (NPV) of 374 of 379 participants (98.7% [95% CI, 96.9%-99.4%]).The test correctly classified 208 of 296 viral infections, for a sensitivity of 70.3% (95% CI, 64.8%-75.2%), a specificity of 176 of 200 participants (88.0% [95% CI, 82.8%-91.8%]), a PPV of 208 of 232 participants (89.7% [95% CI, 85.1%-92.9%]), and an NPV of 176 of 264 participants (66.7% [95% CI, 60.8%-72.1%]). Conclusions and Relevance: In this study, a rapid diagnostic test demonstrated diagnostic performance that may inform clinicians when assessing for bacterial or viral etiology of ARI symptoms.

Longitudinal characterization of circulating neutrophils uncovers phenotypes associated with severity in hospitalized COVID-19 patients.

Mechanisms of neutrophil involvement in severe coronavirus disease 2019 (COVID-19) remain incompletely understood. Here, we collect longitudinal blood samples from 306 hospitalized COVID-19+ patients and 86 controls and perform bulk RNA sequencing of enriched neutrophils, plasma proteomics, and high-throughput antibody profiling to investigate relationships between neutrophil states and disease severity. We identify dynamic switches between six distinct neutrophil subtypes. At days 3 and 7 post-hospitalization, patients with severe disease display a granulocytic myeloid-derived suppressor cell-like gene expression signature, while patients with resolving disease show a neutrophil progenitor-like signature. Humoral responses are identified as potential drivers of neutrophil effector functions, with elevated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific immunoglobulin G1 (IgG1)-to-IgA1 ratios in plasma of severe patients who survived. In vitro experiments confirm that while patient-derived IgG antibodies induce phagocytosis in healthy donor neutrophils, IgA antibodies predominantly induce neutrophil cell death. Overall, our study demonstrates a dysregulated myelopoietic response in severe COVID-19 and a potential role for IgA-dominant responses contributing to mortality.

Clinical decision support improves blood culture collection before intravenous antibiotic administration in the emergency department.

OBJECTIVE: Surviving Sepsis guidelines recommend blood cultures before administration of intravenous (IV) antibiotics for patients with sepsis or moderate to high risk of bacteremia. Clinical decision support (CDS) that reminds emergency department (ED) providers to obtain blood cultures when ordering IV antibiotics may lead to improvements in this process measure. METHODS: This was a multicenter causal impact analysis comparing timely blood culture collections prior to IV antibiotics for adult ED patients 1 year before and after a CDS intervention implementation in the electronic health record. A Bayesian structured time-series model compared daily timely blood cultures collected compared to a forecasted synthetic control. Mixed effects models evaluated the impact of the intervention controlling for confounders. RESULTS: The analysis included 54 538 patients over 2 years. In the baseline phase, 46.1% had blood cultures prior to IV antibiotics, compared to 58.8% after the intervention. Causal impact analysis determined an absolute increase of 13.1% (95% CI 10.4-15.7%) of timely blood culture collections overall, although the difference in patients with a sepsis diagnosis or who met CDC Adult Sepsis Event criteria was not significant, absolute difference 8.0% (95% CI -0.2 to 15.8). Blood culture positivity increased in the intervention phase, and contamination rates were similar in both study phases. DISCUSSION: CDS improved blood culture collection before IV antibiotics in the ED, without increasing overutilization. CONCLUSION: A simple CDS alert increased timely blood culture collections in ED patients for whom concern for infection was high enough to warrant IV antibiotics.

COVID-19 Seroprevalence in ED Health Care Professionals Study: A Cross-Sectional Study.

INTRODUCTION: ED health care professionals are at the frontline of evaluation and management of patients with acute, and often undifferentiated, illness. During the initial phase of the SARS-CoV-2 outbreak, there were concerns that ED health care professionals may have been at increased risk of exposure to SARS-CoV-2 due to difficulty in early identification of patients. This study assessed the seroprevalence of SARS-CoV-2 antibodies among ED health care professionals without confirmed history of COVID-19 infection at a quaternary academic medical center. METHODS: This study used a cross-sectional design. An ED health care professional was deemed eligible if they had worked at least 4 shifts in the adult emergency department from April 1, 2020, through May 31, 2020, were asymptomatic on the day of blood draw, and were not known to have had prior documented COVID-19 infection. The study period was December 17, 2020, to January 27, 2021. Eligible participants completed a questionnaire and had a blood sample drawn. Samples were run on the Roche Cobas Elecsys Anti-SARS-CoV-2 antibody assay. RESULTS: Of 103 health care professionals (16 attending physicians, 4 emergency residents, 16 advanced practice professionals, and 67 full-time emergency nurses), only 3 (2.9%; exact 95% CI, 0.6%-8.3%) were seropositive for SARS-CoV-2 antibodies. DISCUSSION: At this quaternary academic medical center, among those who volunteered to take an antibody test, there was a low seroprevalence of SARS-CoV-2 antibodies among ED clinicians who were asymptomatic at the time of blood draw and not known to have had prior COVID-19 infection.