Immune responses of lung transplant recipients against SARS-CoV-2 and common respiratory coronaviruses: Evidence for pre-existing cross-reactive immunity.

Humoral and cellular immune responses to SARS-CoV-2 and other coronaviruses in lung transplant recipients are unknown. We measured antibodies and T cell responses against the SARS-CoV-2 spike S2 and nucleocapsid antigens and spike antigens from common respiratory coronaviruses (229E, NL63, OC43, and HKU1) after vaccination or infection of LTxRs. 148 LTxRs from single center were included in this study: 98 after vaccination and 50 following SARS-CoV-2 infection. Antibodies were quantified by enzyme-linked immunosorbent assay. The frequency of T cells secreting IL2, IL4, IL10, IL17, TNFα, and IFNγ were enumerated by enzyme-linked immunospot assay. Our results have shown the development of antibodies to SARS-CoV-2 spike protein in infected LTxRs (39/50) and vaccinated LTxRs (52/98). Vaccinated LTxRs had higher number of T cells producing TNFα but less cells producing IFNγ than infected LTxRs in response to the nucleocapsid antigen and other coronavirus spike antigens. We didn't find correlation between the development of antibodies and cellular immune responses against the SARS-CoV-2 spike protein after vaccination. Instead, LTxRs have pre-existing cellular immunity to common respiratory coronaviruses, leading to cross-reactive immunity against SARS-CoV-2 which likely will provide protection against SARS-Cov-2 infection.

Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Utility of COVID-19 antigen testing in the emergency department.

BACKGROUND: The BinaxNOW coronavirus disease 2019 (COVID-19) Ag Card test (Abbott Diagnostics Scarborough, Inc.) is a lateral flow immunochromatographic point-of-care test for the qualitative detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein antigen. It provides results from nasal swabs in 15 minutes. Our purpose was to determine its sensitivity and specificity for a COVID-19 diagnosis. METHODS: Eligible patients had symptoms of COVID-19 or suspected exposure. After consent, 2 nasal swabs were collected; 1 was tested using the Abbott RealTime SARS-CoV-2 (ie, the gold standard polymerase chain reaction test) and the second run on the BinaxNOW point of care platform by emergency department staff. RESULTS: From July 20 to October 28, 2020, 767 patients were enrolled, of which 735 had evaluable samples. Their mean (SD) age was 46.8 (16.6) years, and 422 (57.4%) were women. A total of 623 (84.8%) patients had COVID-19 symptoms, most commonly shortness of breath (n = 404; 55.0%), cough (n = 314; 42.7%), and fever (n = 253; 34.4%). Although 460 (62.6%) had symptoms ≤7 days, the mean (SD) time since symptom onset was 8.1 (14.0) days. Positive tests occurred in 173 (23.5%) and 141 (19.2%) with the gold standard versus BinaxNOW test, respectively. Those with symptoms >2 weeks had a positive test rate roughly half of those with earlier presentations. In patients with symptoms ≤7 days, the sensitivity, specificity, and negative and positive predictive values for the BinaxNOW test were 84.6%, 98.5%, 94.9%, and 95.2%, respectively. CONCLUSIONS: The BinaxNOW point-of-care test has good sensitivity and excellent specificity for the detection of COVID-19. We recommend using the BinasNOW for patients with symptoms up to 2 weeks.

Cutting Edge: Circulating Exosomes with COVID Spike Protein Are Induced by BNT162b2 (Pfizer-BioNTech) Vaccination prior to Development of Antibodies: A Novel Mechanism for Immune Activation by mRNA Vaccines.

Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) causes severe acute respiratory syndrome. mRNA vaccines directed at the SARS-CoV-2 spike protein resulted in development of Abs and protective immunity. To determine the mechanism, we analyzed the kinetics of induction of circulating exosomes with SARS-CoV-2 spike protein and Ab following vaccination of healthy individuals. Results demonstrated induction of circulating exosomes expressing spike protein on day 14 after vaccination followed by Abs 14 d after the second dose. Exosomes with spike protein, Abs to SARS-CoV-2 spike, and T cells secreting IFN-γ and TNF-α increased following the booster dose. Transmission electron microscopy of exosomes also demonstrated spike protein Ags on their surface. Exosomes with spike protein and Abs decreased in parallel after four months. These results demonstrate an important role of circulating exosomes with spike protein for effective immunization following mRNA-based vaccination. This is further documented by induction of humoral and cellular immune responses in mice immunized with exosomes carrying spike protein.

Rapid Emergency Department Heart Failure Outpatients Trial (REDHOT II): a randomized controlled trial of the effect of serial B-type natriuretic peptide testing on patient management.

BACKGROUND: B-type natriuretic peptide is useful to diagnose heart failure. We determined whether the use of serial B-type natriuretic peptide measurements to guide treatment improves the outcome in patients with acute heart failure. METHODS AND RESULTS: We conducted a randomized controlled trial of patients with acute heart failure in 10 academic and community emergency departments. The experimental group received serial B-type natriuretic peptide testing (at 3, 6, 9, and 12 hours then daily). The control group received usual care. Our outcomes were hospital length of stay, 30-day readmission rate, and all-cause mortality. There were 219 controls and 228 experimental patients. Mean age was 64 years, 49% were women, 58% were blacks, and 34% were whites. Groups were similar in baseline characteristics. Comparing the serial testing with the control group, there was no difference in length of stay (6.5 days [95% CI, 5.2 to 7.9] versus 6.5 days [95% CI, 5.6 to 7.3]; difference, 0.1 [95% CI, -1.7 to 1.5]), in-hospital mortality (2.2% [95% CI, 0.9 to 5.0] versus controls, 3.2% [95% CI, 1.6 to 6.5]; difference, 1.0% [95% CI, -2.3 to 4.5]), 30-day mortality (3.7% [95% CI, 1.8 to 7.5] versus 5.5% [95% CI, 3.0 to 9.8]; difference, 1.8% [95% CI, -2.8 to 6.5]), or hospital revisit rate (20.2% [95% CI, 15.0 to 26.6] versus 23.7% [95% CI, 18.0 to 30.6]; difference, 3.5% [95% CI, -5.1 to 12.1]). CONCLUSIONS: In this study of 447 patients hospitalized for suspected heart failure, we were unable to demonstrate a benefit of serial testing with B-type natriuretic peptide in terms of hospital length of stay, mortality, or readmission rate.

The Internet Tracking Registry of Acute Coronary Syndromes (i*trACS): a multicenter registry of patients with suspicion of acute coronary syndromes reported using the standardized reporting guidelines for emergency department chest pain studies.

STUDY OBJECTIVE: Observational studies of well-described patient populations presenting to emergency departments (EDs) with suspicion of acute coronary syndrome are necessary to understand the relationships between patients' signs and symptoms, cardiac risk profile, test results, practice patterns, and outcomes. We describe the methods for data collection and the ED population enrolled in a multicenter registry of patients with chest pain. METHODS: Patients older than 18 years, presenting to one of 8 EDs in the United States or 1 ED in Singapore, and with possible acute coronary syndrome were enrolled in the Internet Tracking Registry of Acute Coronary Syndromes between June 1999 and August 2001. Prospective data, including presenting signs and symptoms, ECG findings, and the ED physician's initial impression of risk, were systematically collected. Medical record review or daily follow-up was used to obtain cardiac biomarker results, invasive and noninvasive testing, treatments, procedures, and inhospital outcomes. Thirty-day outcomes were determined by telephone follow-up and medical record review. RESULTS: The registry includes 15,608 patients, with 17,713 visits. Chest pain was the chief complaint in 71% of visits. The ECG was diagnostic of ischemia or infarction in 10.1% and positive cardiac biomarkers were observed in 10% of visits. Forty-three percent of patients were sent home directly from the ED. Of admitted patients, 5% died by 30 days, and 3% had documented coronary artery disease or had undergone percutaneous coronary intervention or coronary artery bypass grafting within 30 days. For patients discharged directly from the ED, 0.4% died or had a documented myocardial infarction within 30 days. Coronary artery bypass graft surgery, percutaneous coronary intervention, or a diagnosis of coronary artery disease was found in 0.5% of discharged patients. CONCLUSION: A unique description of undifferentiated ED chest pain patients with suspected acute coronary syndrome is provided. The data set can be used to generate and explore hypotheses to improve understanding of the complex relationships between presentation, treatment, testing, intervention and outcomes.

Performance of a population-based cardiac risk stratification tool in Asian patients with chest pain.

OBJECTIVES: Most contemporary cardiac risk stratification tools have been derived and validated in mixed-race populations. Their validity in single-race populations has not been tested. The authors sought to compare the performance of a risk stratification tool between a mixed-race U.S. patient population and an Asian patient population. METHODS: This study is an analysis of data from the Internet Tracking Registry for Acute Coronary Syndromes (i(*)trACS) registry of patients with chest pain presenting to the emergency departments of eight U.S. centers and one site in Singapore. The Acute Cardiac Ischemia Time-Insensitive Predictive Instrument (ACI-TIPI) was computed for included patients, and its performance in predicting acute coronary syndrome (ACS) was compared between patients from the United States and Singapore. RESULTS: Of the 11,991 included patients, 1,120 experienced ACS. Although the ACI-TIPI demonstrated similar accuracy among groups (area under the curve, 0.729 [U.S.] vs. 0.719 [Singapore]; p = 0.5611), sensitivity and specificity were different when equal ACI-TIPI thresholds were considered. Recreating the logistic regression models used to create the ACI-TIPI showed similar results between the derived parameters and the parameters estimated for the U.S. group. In contrast, age older than 50 years (log-odds ratio [LOR], 0.107; 95% confidence interval [CI] = 0.518 to 0.713), male gender (LOR, 0.487; 95% CI = 0.149 to 1.122), and chest pain as a primary complaint (LOR, 0.237; 95% CI = 0.139 to 0.613) had little predictive power in patients from Singapore. CONCLUSIONS: Differences exist in presentation and factors associated with ACS among patients from the United States and Singapore that may affect the performance of risk stratification tools. These findings suggest that cardiac clinical decision rules need international validation.

Is the initial diagnostic impression of "noncardiac chest pain" adequate to exclude cardiac disease?

STUDY OBJECTIVE: In patients presenting to the emergency department (ED) with an initial diagnostic impression of noncardiac chest pain, we determine the 30-day incidence of adverse cardiac events and characteristics associated with those events. METHODS: The multicenter, prospectively collected Internet Tracking Registry for Acute Coronary Syndromes (i*tr ACS ) registry of patients with chest pain enrolled from June 1, 1999, to August 1, 2001, was reviewed. We included patients if the physician's initial diagnostic impression was noncardiac chest pain after the medical history, physical examination, and initial 12-lead ECG. ED records, inpatient records, and follow-up results were reviewed for evidence of an adverse cardiac event defined as ST-segment or non-ST-segment elevation myocardial infarction, unstable angina, revascularization, or cardiac death within 30 days. RESULTS: Of 17,737 patients enrolled in i*tr ACS , 2,992 had an initial emergency physician impression of noncardiac chest pain. Of these, 85 (2.8%) patients had definite evidence for an adverse cardiac event. The adverse cardiac event group was older (61.2 versus 47.9 years), more likely to be men (58.6% versus 38.7%), and had a higher Acute Cardiac Ischemia-Time Insensitive Predictive Instrument score (26.1 versus 15.6). Factors associated with adverse cardiac events included hypercholesterolemia, diabetes, history of coronary artery disease, and history of congestive heart failure. CONCLUSION: When the initial impression is noncardiac chest pain, high-risk features such as traditional cardiovascular risk factors or a history of coronary artery disease are associated with adverse cardiac events. In the absence of well-defined criteria, treating physicians should consider further evaluation before diagnosing patients with noncardiac chest pain if these features are present.

Insurance status and the treatment of myocardial infarction at academic centers.

UNLABELLED: Numerous studies have documented treatment disparities in patients with acute coronary syndromes based on race and gender. Other causes for treatment disparities may exist. OBJECTIVES: To determine if insurance status affects quality of care in patients with acute myocardial infarction (AMI) presenting to academic health centers. METHODS: The Internet Tracking Registry for Acute Coronary Syndromes (i*trACS), a prospective multicenter registry of patients with chest pain presenting to the emergency department who receive an electrocardiogram, was used as the database (N = 17,737). A subset of patients who were diagnosed as having AMI were selected from the database (n = 936). Patients were classified as having either ST-segment elevation MI (n = 178) or non-ST-segment elevation MI (n = 758). Insurance status, age, race, and gender were extracted as predictor variables. The influence of predictor variables on treatment modality was investigated using logistic regression, adjusted for clustering within sites. RESULTS: The odds of a self-pay patient with ST-segment elevation MI receiving fibrinolytics were 3.23 (95% CI = 1.56 to 6.69) times higher than for other patients. Patients with Medicare coverage were less likely to receive fibrinolytics (odds ratio [OR] 0.35, 95% CI = 0.19 to 0.65) and tended to undergo percutaneous coronary intervention less often (OR 0.60, 95% CI = 0.36 to 1.01). The odds of a privately insured patient's receiving coronary artery bypass grafting (OR 2.76, 95% CI = 1.62 to 4.72) or percutaneous coronary intervention (OR 1.47, 95% CI = 1.03 to 2.11) were higher than for other patients. CONCLUSIONS: Insurance coverage appears to affect treatment in patients with AMI, with self-pay patients more likely to receive less-expensive therapies and insured patients more likely to receive invasive treatments.

Tetanus immunity and physician compliance with tetanus prophylaxis practices among emergency department patients presenting with wounds.

STUDY OBJECTIVE: We determine tetanus seroprotection rates and physician compliance with tetanus prophylaxis recommendations among patients presenting with wounds. METHODS: A prospective observational study of patients aged 18 years or older who presented to 5 university-affiliated emergency departments (EDs) because of wounds was conducted between March 1999 and August 2000. Serum antitoxin levels were measured by enzyme immunoassay with seroprotection defined as more than 0.15 IU/mL. Seroprotection rates, risk factors for lack of seroprotection, and rates of physician compliance with tetanus prophylaxis recommendations by the Advisory Committee on Immunization Practices were determined. RESULTS: The seroprotection rate among 1,988 patients was 90.2% (95% confidence interval 88.8% to 91.5%). Groups with significantly lower seroprotection rates were persons aged 70 years or older, 59.5% (risk ratio [RR] 5.2); immigrants from outside North America or Western Europe, 75.3% (RR 3.7); persons with a history of inadequate immunization, 86.3% (RR 2.9); and persons without education beyond grade school, 76.5% (RR 2.5). Despite a history of adequate immunization, 18% of immigrants lacked seroprotection. Overall, 60.9% of patients required tetanus immunization, of whom 57.6% did not receive indicated immunization. Among patients with tetanus-prone wounds, appropriate prophylaxis (ie, tetanus immunoglobulin and toxoid) was provided to none of 504 patients who gave a history of inadequate primary immunization (of whom 15.1% had nonprotective antibody titers) and to 218 (79%) of 276 patients who required only a toxoid booster. CONCLUSION: Although seroprotection rates are generally high in the United States, the risk of tetanus persists in the elderly, immigrants, and persons without education beyond grade school. There is substantial underimmunization in the ED (particularly with regard to use of tetanus immunoglobulin), leaving many patients, especially those from high-risk groups, unprotected. Better awareness of tetanus prophylaxis recommendations is necessary, and future tetanus prophylaxis recommendations may be more effective if they are also based on demographic risk factors.

The impact of race on the acute management of chest pain.

OBJECTIVES: African Americans with acute coronary syndromes receive cardiac catheterization less frequently than whites. The objective was to determine if such disparities extend to acute evaluation and non interventional treatment. METHODS: Data on adults with chest pain (N = 7,935) presenting to eight emergency departments (EDs) were evaluated from the Internet Tracking Registry of Acute Coronary Syndromes. Groups were selected from final ED diagnosis: 1) acute myocardial infarction (AMI), n = 400; 2) unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI), n = 1,153; and 3) nonacute coronary syndrome chest pain (non-ACS CP), n = 6,382. American College of Cardiology/American Heart Association guidelines for AMI and UA/NSTEMI were used to evaluate racial disparities with logistic regression models. Odds ratios (ORs) were adjusted for age, gender, guideline publication, and insurance status. Non-ACS CP patients were assessed by comparing electrocardiographic (ECG)/laboratory evaluation, medical treatment, admission rates, and invasive and noninvasive testing for coronary artery disease (CAD). RESULTS: African Americans with UA/NSTEMI received glycoprotein IIb/IIIa receptor inhibitors less often than whites (OR, 0.41; 95% CI = 0.19 to 0.91). African Americans with non-ACS CP underwent ECG/laboratory evaluation, medical treatment, and invasive and noninvasive testing for CAD less often than whites (p < 0.05). Other nonwhites with non-ACS CP were admitted and received invasive testing for CAD less often than whites (p < 0.01). African Americans and other nonwhites with AMI underwent catheterization less frequently than whites (OR, 0.45; 95% CI = 0.29 to 0.71 and OR, 0.40; 95% CI = 0.17 to 0.92, respectively). A similar disparity in catheterization was noted in UA/NSTEMI therapy (OR, 0.53; 95% CI = 0.40 to 0.68 and OR, 0.68; 95% CI = 0.47 to 0.99). CONCLUSIONS: Racial disparities in acute chest pain management extend beyond cardiac catheterization. Poor compliance with recommended treatments for ACS may be an explanation.

Prospective evaluation of emergency department patients with potential coronary syndromes using initial absolute CK-MB vs. CK-MB relative index.

We compared the predictive properties of an initial absolute creatine kinase-MB (CK-MB) to creatine kinase-MB relative index (CK-MB RI) for detecting acute myocardial infarction (AMI), acute coronary syndromes (ACS), and serious cardiac events (SCE). Consecutive patients > 24 years of age with chest pain who received an electrocardiogram (EKG) as part of their Emergency Department (ED) evaluation had CK and CK-MB drawn at presentation. Patients were followed prospectively during their hospital course. The main outcome was AMI, ACS or SCE (death, AMI, dysrhythmias, CHF, PTCA/stent, CABG) within 30 days. The sensitivity, specificity, PPV and NPV of CK-MB and CK-MB RI to predict AMI, ACS, and SCE were calculated with 95% CIs. We enrolled 2028 patients. There were 105 patients (5.2%) with AMI, 266 (13.1%) with ACS, and 150 with SCE (7.4%). Absolute CK-MB had a higher sensitivity than CK-MB RI for AMI (52.0 vs. 46.9, respectively), ACS (23.5 vs. 20.8, respectively), and SCE (39.6 vs. 36.0, respectively), but a lower specificity than CK-MB RI for AMI (93.2 vs. 96.1, respectively), ACS (93.1 vs. 96.1, respectively) and SCE (93.3 vs. 96.3, respectively); and lower PPV for AMI (35.7 vs. 46.5, respectively), ACS (42.0 vs. 53.4, respectively) and SCE (38.5 vs. 50.5, respectively). The negative predictive values were similar for all outcomes. We conclude that the risk stratification of ED chest pain patients by absolute CK-MB has higher sensitivity, similar NPV, but a lower specificity and PPV than CK-MB relative index for detection of AMI, ACS, and SCE. The optimal test depends upon the relative importance of the sensitivity or specificity for clinical decision-making in an individual patient.

Can electrocardiographic criteria predict adverse cardiac events and positive cardiac markers?

OBJECTIVES: To determine electrocardiogram (ECG) predictors of positive cardiac markers and short-term adverse cardiac events in an undifferentiated chest pain population presenting to emergency departments (EDs). The authors hypothesized that specific ECG findings, other than those previously identified in higher-risk populations, would be predictive of cardiac outcomes and positive cardiac markers. METHODS: This study used data from a prospectively collected, retrospectively analyzed Internet-based data registry of undifferentiated chest pain patients (i*trACS). Logistic regression modeling was performed to determine the ECG findings that were predictive of 1) positive cardiac markers and 2) short-term adverse cardiac events. RESULTS: ST-segment elevation (STE), ST-segment depression (STD), pathological Q-waves (PQW), and T-wave inversion were associated with increased odds of percutaneous coronary intervention or catheterization, myocardial infarction, or coronary artery bypass grafting. The odds of creatine kinase-MB (CK-MB) measuring positive were increased if STE, STD, or PQW were present [odds ratio (OR) 2.495, 2.582, and 1.295, respectively]. A right bundle branch block tended to decrease the odds of CK-MB measuring positive (OR 0.658). A similar pattern of results was observed for troponin I (OR 3.608 for STE, 3.72 for STD, 1.538 for PQW). Troponin T showed an increased odds of measuring positive if any of STE, STD, left bundle branch block, or T-wave inversion were evident (OR 2.313, 2.816, 1.80, and 1.449, respectively). CONCLUSIONS: Initial ECG criteria can be used to predict short-term cardiac outcomes and positive cardiac markers. These findings can be important aids in the risk-stratification and aggressive treatment regimens of chest pain patients presenting to EDs.