Johnson, Patrick W.

Abstract Immunosuppressed patients may be at high risk for breakthrough COVID-19 infection despite SARS-CoV-2 vaccination, due to an inadequate or negligible antibody response. Based on data from the Leukemia & Lymphoma Society (LLS) National Registry, 25% of patients with hematologic malignancies do not produce anti-Spike protein antibodies in response to mRNA vaccines, with B-cell malignancy patients at highest risk (Greenberger et al, 2021, Cancer Cell, on-line). While studies of T-cell immunity, antibody cocktails, and booster vaccinations are underway, some patients have elected to receive an additional "booster" vaccination after a full course of SARS-CoV-2 vaccination. The LLS National Registry (NCT04794387) has collected Patient Reported Outcomes and serology from 3300 patients with hematologic malignancies. This study was approved by the Western Institutional Review Board, and participants provided informed consent electronically. As of July 2021, the Registry includes 24 patients who obtained a 3 rd vaccination after full vaccination with mRNA vaccines. Twenty of these patients were seronegative >14 days post 2 nd vaccination (as measured by the Roche Elecsys assay). Four patients had low positive serology results. All patients were nucleocapsid antibody negative. Patient ages ranged from 51-79 years. Eleven had chronic lymphocytic leukemia (CLL), 7 non-Hodgkin's lymphoma (NHL), 5 Waldenstrom's macroglobulinemia (WM), and 1 multiple myeloma (MM). Six patients were not currently on anti-B cell therapy, 11 had received anti-CD20 therapy (8 within the last 6 months), 6 had received Bruton's tyrosine kinase (BTK) inhibitors within the last 6 months, and 1 patient had recently received chemotherapy. The booster vaccinations were obtained between April and June 2021, 21 to 114 days after completing the initial vaccination series between January and April 2021. Serology was performed 12-61 days post-booster vaccination. Fifteen patients received a heterologous adenovirus vaccine. Four patients received a heterologous mRNA vaccine, 5 patients received a homologous mRNA vaccine. Descriptive results are shown on the following table. All patients (4) who had some level of antibody response to the initial vaccines had an augmented antibody response after a booster (i.e. sero-enhanced). Patients who had prior anti-CD20 often failed to seroconvert after booster vaccination. Only 2 of 8 patients who received anti-CD20 antibody treatment in the 6 months prior to vaccination seroconverted after booster vaccination. Two out of 3 seronegative patients receiving anti-CD20 therapy in the last 2 years (but > 6 months) seroconverted after the booster. One patient with follicular lymphoma who received anti-CD20 therapy in 2019 remained seronegative despite a prolonged duration without therapy. Of the 6 seronegative patients taking BTK inhibitors, 3 seroconverted after the booster. Two of the 3 remaining seronegative patients were taking concomitant anti-CD20 therapy. Of the 4 seronegative patients not currently taking anti-B cell therapy, 3 seroconverted while one patient who currently required intravenous immunoglobulin remained seronegative. A patient currently receiving chemotherapy also did not respond to a booster. In this limited set of patients there was no evident pattern of antibody response amongst patients who received homologous versus heterologous vaccine nor between disease types. While anti-CD20 therapy appeared to reduce antibody response to booster vaccination, there was substantial heterogeneity. Although many patients with B-cell malignancies did not mount a robust response to full mRNA vaccine series, several patients demonstrated an antibody response to the booster vaccination. Clinical trials are needed to further understand who can benefit from a booster strategy as well as define the safety of the approach. The LLS Registry includes collection of Electronic Health Records, which will allow us to more specifically evaluate timing and dosage of boosters, the influence of prior therapeutics, as well as health and safety outcomes to better guide patients and physicians through the COVID-19 pandemic. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Booster vaccination (after full vaccination) using BNT162b2, mRNA-1273, or Ad26.COV2.S

Abstract Background Cardiovascular disease (CVD) has been identified as a major threat to maternal health in the US and UK with cardiomyopathy being one of the most common acquired CVD in the pregnant and postpartum period. Diagnosing cardiomyopathy in pregnancy is challenging due to an overlap of cardiovascular symptoms with normal pregnancy symptoms. Purpose The purpose of this study was to evaluate the effectiveness of an ECG based deep learning model in identifying cardiomyopathy among pregnant and postpartum women. Methods We utilized an ECG based deep learning model to detect cardiomyopathy in a cohort of pregnant or postpartum women seen at multiple hospital sites. Model performance was evaluated using area under the curve (AUC), accuracy, sensitivity, and specificity. We compared the diagnostic probabilities of the deep learning model with natriuretic peptides and a multivariable model consisting of demographic and clinical parameters. Results 1,807 women were included. 7%, 10% and 13% had LVEF ≤35%, <45% and <50% respectively. The ECG based deep learning model identified cardiomyopathy with an AUC of 0.92 for left ventricular ejection fraction (LVEF) ≤35%, 0.89 for LVEF <45% and 0.87 for LVEF <50%. For LVEF ≤35%, AUC was higher in Black (0.95) and Hispanic (0.98) women compared to white (0.91). Natriuretic peptides and the multivariable model had AUCs of 0.85 and 0.72 respectively. Conclusions A deep learning model effectively identifies cardiomyopathy in pregnant or postpartum women, outperforms natriuretic peptides and traditional clinical parameters with the potential to become a powerful initial screening tool for cardiomyopathy in the obstetric care setting. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): This study was made possible using resources supported by the Mayo Clinic Women's Health Research Center and the Mayo Clinic Building Interdisciplinary Research Careers in Women's Health (BIRCWH) Program funded by the National Institutes of Health (NIH), grant number K12 HD065987. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Abstract Aims Cardiovascular disease is a major threat to maternal health, with cardiomyopathy being among the most common acquired cardiovascular diseases during pregnancy and the postpartum period. The aim of our study was to evaluate the effectiveness of an electrocardiogram (ECG)-based deep learning model in identifying cardiomyopathy during pregnancy and the postpartum period. Methods and results We used an ECG-based deep learning model to detect cardiomyopathy in a cohort of women who were pregnant or in the postpartum period seen at Mayo Clinic. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. We compared the diagnostic probabilities of the deep learning model with natriuretic peptides and a multivariable model consisting of demographic and clinical parameters. The study cohort included 1807 women; 7%, 10%, and 13% had left ventricular ejection fraction (LVEF) of 35% or less, <45%, and <50%, respectively. The ECG-based deep learning model identified cardiomyopathy with AUCs of 0.92 (LVEF ≤ 35%), 0.89 (LVEF < 45%), and 0.87 (LVEF < 50%). For LVEF of 35% or less, AUC was higher in Black (0.95) and Hispanic (0.98) women compared to White (0.91). Natriuretic peptides and the multivariable model had AUCs of 0.85 to 0.86 and 0.72, respectively. Conclusions An ECG-based deep learning model effectively identifies cardiomyopathy during pregnancy and the postpartum period and outperforms natriuretic peptides and traditional clinical parameters with the potential to become a powerful initial screening tool for cardiomyopathy in the obstetric care setting.

Longitudinal studies assessing durability of the anti-severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2) humoral immune response have generated conflicting results. This has been proposed to be due to differences in patient populations, the lack of standardized methodologies, and the use of assays that measure distinct aspects of the humoral response.

Background: The US Food and Drug Administration authorized COVID-19 convalescent plasma (CCP) therapy for hospitalized COVID-19 patients via the Expanded Access Program (EAP) and the Emergency Use Authorization (EUA), leading to use in about 500,000 patients during the first year of the pandemic for the USA. Methods: We tracked the number of CCP units dispensed to hospitals by blood banking organizations and correlated that usage with hospital admission and mortality data. Results: CCP usage per admission peaked in Fall 2020, with more than 40% of inpatients estimated to have received CCP between late September and early November 2020. However, after randomized controlled trials failed to show a reduction in mortality, CCP usage per admission declined steadily to a nadir of less than 10% in March 2021. We found a strong inverse correlation (r = −0.52, p=0.002) between CCP usage per hospital admission and deaths occurring 2 weeks after admission, and this finding was robust to examination of deaths taking place 1, 2, or 3 weeks after admission. Changes in the number of hospital admissions, SARS-CoV-2 variants, and age of patients could not explain these findings. The retreat from CCP usage might have resulted in as many as 29,000 excess deaths from mid-November 2020 to February 2021. Conclusions: A strong inverse correlation between CCP use and mortality per admission in the USA provides population-level evidence consistent with the notion that CCP reduces mortality in COVID-19 and suggests that the recent decline in usage could have resulted in excess deaths. Funding: There was no specific funding for this study. AC was supported in part by RO1 HL059842 and R01 AI1520789; MJJ was supported in part by 5R35HL139854. This project has been funded in whole or in part with Federal funds from the Department of Health and Human Services; Office of the Assistant Secretary for Preparedness and Response; Biomedical Advanced Research and Development Authority under Contract No. 75A50120C00096.

AbstractIn the absence of effective countermeasures, human convalescent plasma has been widely used to treat severe acute respiratory syndrome coronavirus 2, the causative agent of novel coronavirus disease 19 (COVID‐19), including among patients with innate or acquired immunosuppression. However, the association between COVID‐19‐associated mortality in patients with immunosuppression and therapeutic use of convalescent plasma is unknown. We review 75 reports, including one large matched‐control registry study of 143 COVID‐19 patients with hematological malignancies, and 51 case reports and 23 case series representing 238 COVID‐19 patients with immunosuppression. We review clinical features and treatment protocols of COVID‐19 patients with immunosuppression after treatment with human convalescent plasma. We also discuss the time course and clinical features of recovery. The available data from case reports and case series provide evidence suggesting a mortality benefit and rapid clinical improvement in patients with several forms of immunosuppression following COVID‐19 convalescent plasma transfusion. The utility of convalescent plasma or other forms of antibody therapy in immune‐deficient and immune‐suppressed patients with COVID‐19 warrants further investigation.

Abstract Aims Early detection of aortic stenosis (AS) is becoming increasingly important with a better outcome after aortic valve replacement in asymptomatic severe AS patients and a poor outcome in moderate AS. We aimed to develop artificial intelligence-enabled electrocardiogram (AI-ECG) using a convolutional neural network to identify patients with moderate to severe AS. Methods and results Between 1989 and 2019, 258 607 adults [mean age 63 ± 16.3 years; women 122 790 (48%)] with an echocardiography and an ECG performed within 180 days were identified from the Mayo Clinic database. Moderate to severe AS by echocardiography was present in 9723 (3.7%) patients. Artificial intelligence training was performed in 129 788 (50%), validation in 25 893 (10%), and testing in 102 926 (40%) randomly selected subjects. In the test group, the AI-ECG labelled 3833 (3.7%) patients as positive with the area under the curve (AUC) of 0.85. The sensitivity, specificity, and accuracy were 78%, 74%, and 74%, respectively. The sensitivity increased and the specificity decreased as age increased. Women had lower sensitivity but higher specificity compared with men at any age groups. The model performance increased when age and sex were added to the model (AUC 0.87), which further increased to 0.90 in patients without hypertension. Patients with false-positive AI-ECGs had twice the risk for developing moderate or severe AS in 15 years compared with true negative AI-ECGs (hazard ratio 2.18, 95% confidence interval 1.90–2.50). Conclusion An AI-ECG can identify patients with moderate or severe AS and may serve as a powerful screening tool for AS in the community.

Background: Heart rate–corrected QT interval (QTc) prolongation, whether secondary to drugs, genetics including congenital long QT syndrome, and/or systemic diseases including SARS-CoV-2–mediated coronavirus disease 2019 (COVID-19), can predispose to ventricular arrhythmias and sudden cardiac death. Currently, QTc assessment and monitoring relies largely on 12-lead electrocardiography. As such, we sought to train and validate an artificial intelligence (AI)–enabled 12-lead ECG algorithm to determine the QTc, and then prospectively test this algorithm on tracings acquired from a mobile ECG (mECG) device in a population enriched for repolarization abnormalities. Methods: Using >1.6 million 12-lead ECGs from 538 200 patients, a deep neural network (DNN) was derived (patients for training, n = 250 767; patients for testing, n = 107 920) and validated (n = 179 513 patients) to predict the QTc using cardiologist-overread QTc values as the “gold standard”. The ability of this DNN to detect clinically-relevant QTc prolongation (eg, QTc ≥500 ms) was then tested prospectively on 686 patients with genetic heart disease (50% with long QT syndrome) with QTc values obtained from both a 12-lead ECG and a prototype mECG device equivalent to the commercially-available AliveCor KardiaMobile 6L. Results: In the validation sample, strong agreement was observed between human over-read and DNN-predicted QTc values (−1.76±23.14 ms). Similarly, within the prospective, genetic heart disease–enriched dataset, the difference between DNN-predicted QTc values derived from mECG tracings and those annotated from 12-lead ECGs by a QT expert (−0.45±24.73 ms) and a commercial core ECG laboratory [10.52±25.64 ms] was nominal. When applied to mECG tracings, the DNN’s ability to detect a QTc value ≥500 ms yielded an area under the curve, sensitivity, and specificity of 0.97, 80.0%, and 94.4%, respectively. Conclusions: Using smartphone-enabled electrodes, an AI DNN can predict accurately the QTc of a standard 12-lead ECG. QTc estimation from an AI-enabled mECG device may provide a cost-effective means of screening for both acquired and congenital long QT syndrome in a variety of clinical settings where standard 12-lead electrocardiography is not accessible or cost-effective.