Therapeutic considerations for prevention and treatment of thrombotic events in COVID-19

Thrombosis is a known complication of SARS-CoV-2 infection, particularly within a severely symptomatic subset of patients with COVID-19 disease, in whom an aggressive host immune response leads to cytokine storm syndrome (CSS). The incidence of thrombotic events coinciding with CSS may contribute to the severe morbidity and mortality observed in association with COVID-19. This review provides an overview of pharmacologic approaches based upon an emerging understanding of the mechanisms responsible for thrombosis across a spectrum of COVID-19 disease involving an interplay between immunologic and pro-thrombotic events, including endothelial injury, platelet activation, altered coagulation pathways, and impaired fibrinolysis. © 2022

Immunogenicity, efficacy and safety of mRNA-COVID-19 vaccines in people with multiple sclerosis

Introduction: Knowledge regarding the development of protective immunity after COVID-19 vaccines is needed to guide medical, political and public health measures against the current and future pandemics. Objectives and Aims: To characterise and compare the safety, immunogenicity and efficacy of mRNA-COVID-19 vaccines in people with multiple sclerosis (pwMS) and healthy controls (HCs). Method(s): All pwMS vaccinated against COVID-19 in Norway were invited to participate in an ongoing observational cohort study (NevroVAX) from March 2021. Demographic-, immunisation-and disease-specific data were acquired from patient journals, web-questionnaires, the Norwegian Immunization Registry and Surveillance System for Communicable Diseases. Antibodies to full length spike protein and the receptor-binding domain (RBD) from SARS-CoV-2 were measured using a bead-based flow cytometric assay, while cellular immunity was investigated using high dimensional multiparameter analyses. Results and Conclusion(s): To date, 5545 pwMS were included with results available regarding humoral responses in 3021 (mean follow-up time 257 days), cellular responses in 140, and clinical efficacy in 900 pwMS. Those treated with anti-CD20 therapy or sphingosine-1-phosphate receptor modulators (S1PM) had weak humoral immune responses after two doses of mRNA-COVID-19 vaccines (80% and 91% <200 BAU/ml, respectively). Additional vaccine doses were safe and associated with a modest increase of anti-SARS-CoV-2 spike RBD IgG antibodies (72% and 83% <200 BAU/ml after three, 74% and 89% <200 BAU/ml after four doses). Humoral responses were weaker after all vaccine doses in pwMS (also in those without treatment) compared to HCs. Cellular responses were significantly attenuated in pwMS treated with S1PM. An elevated rate of non-omicron breakthrough infections was observed in the anti-CD20 (19%), S1PM (18%), and HSCT (14%) group, compared to pwMS on other high-or low-efficacy DMTs or without treatment (13%, 10%, and 7%, respectively). Among 900 pwMS treated at the same hospital, 12 (1%) were hospitalized due to COVID-19, one requiring intensive care. Our results show that antibody responses correlated with the rate of breakthrough infections but is not necessarily indicative of a failed cellular or clinical response to vaccination, and that pwMS have weaker humoral responses than HCs regardless of treatment status. Updated, real-world data from NevroVAX will be presented at ECTRIMS 2022.

INVESTIGATING HETEROGENEITY OF TREATMENT EFFECT FOR CONVALESCENT PLASMA IN SEVERE COVID-19: SECONDARY ANALYSIS OF A RANDOMIZED CONTROLLED TRIAL

SESSION TITLE: Acute COVID-19 and Beyond: from Hospital to Homebound SESSION TYPE: Original Investigations PRESENTED ON: 10/18/2022 02:45 pm - 03:45 pm PURPOSE: Minimally-biased clustering (MBC) has identified hypoinflammatory (hypo-I) and hyperinflammatory (hyper-I) subphenotypes in ARDS. The hyper-I type exhibits higher inflammatory markers, clinical severity, and mortality. Similar subphenotypes were recently identified in COVID-19-related ARDS. Lower PCR cycle threshold was associated with higher mortality in the hypo-I type, implying an association between viral load (VL) and clinical outcomes in patients with dampened inflammatory responses. In a recent randomized clinical trial (RCT), convalescent plasma (CP) improved survival in severe COVID-19. We hypothesized that the anti-viral effect of CP would more significantly benefit patients without acute hyperinflammation, for whom VL may be associated with mortality. METHODS: From 4/2020-11/2020, 223 adults >18 years of age in New York and Rio de Janeiro with laboratory-confirmed severe COVID-19 were enrolled in a double-blind RCT evaluating the efficacy of CP. 150 patients received CP;73 received control plasma. Hierarchical clustering (HC) of clinical and laboratory data was used to identify sub-groups in the study population. Primary and secondary outcomes were clinical status at 28 days by modified WHO ordinal score (higher scores indicating worse status) and 28-day mortality. Welch’s t-tests, chi-squared tests, and Fisher’s exact tests were used to compare clinical and laboratory data across clusters. Proportional odds and logistic regression were used to assess the association between cluster-derived subgroups and outcome and the interaction between subgroups and randomized treatment assignment. RESULTS: HC identified two clusters (C1;N=156 and C2;N=67) in the population. Patients in C2 had significantly higher markers of inflammation (sedimentation rate, C-reactive protein, interleukin-6), coagulation (D-dimer), and cardiac injury (cardiac troponin) as well as relative lymphopenia, hypoalbuminemia, and lower bicarbonate. At 28 days, patients in C2 had significantly worse clinical status (OR of 1-pt ordinal score increase 3.10, 95% CI 1.72-5.60, p=0.0002) and higher mortality (28.4% vs. 11.5%, OR 3.03, 95% CI 1.47-6.26, p=0.003). There was no significant between-cluster heterogeneity of CP treatment effect on either ordinal score (OR 0.56, 95% CI 0.16-1.95, p=0.36) or mortality (OR 0.52, 95% CI 0.12-2.30, p=0.38). CONCLUSIONS: C2 exhibited elevated inflammatory markers and lymphopenia indicative of an acute hyperinflammatory response. C2 exhibited poorer clinical status and higher mortality at 28 days. There was no evidence of significant heterogeneity of CP treatment effect on 28-day clinical outcomes. CLINICAL IMPLICATIONS: The previously shown mortality benefit of CP in severe COVID may not differ based on inflammatory state. Using MBC methods on larger samples, e.g., patient data from a meta-analysis of CP trials, may reveal a significant impact of inflammatory state on CP effect. DISCLOSURES: No relevant relationships by Matthew Cummings Received a grant sub-award from Amazon relationship with Amazon Please note: 4/2020 -12/2020 Added 03/10/2022 by Max O'Donnell, value=Grant/Research Support No relevant relationships by Tejus Satish No relevant relationships by Allison Wolf

Chicago Pediatric Firearm Deaths During the COVID-19 Pandemic

Background: Pediatric firearm injuries are a major cause of morbidity and mortality. Due to the COVID-19 pandemic, residents of Chicago were placed under a “stay at home” order during the Spring of 2020. The full impact of these “stay at home” orders is unknown, but previous social and economic stressors have been associated with increased rates of violence. Additionally, studies demonstrate increased firearm purchases during this time period, a known risk factor for homicide and suicide. We sought to describe pediatric firearm associated deaths in Chicago during the COVID-19 pandemic and “stay at home” order. Methods: We conducted a retrospective review of the Cook County Medical Examiner's database from January 2016 through December 2020. We collected information on all firearm associated deaths for persons less than 18 years old and compared deaths from 2020 during the COVID-19 Pandemic and Chicago's “stay at home” order to deaths from the previous 4 years to determine if there were differences that occurred during these time periods. Results: During the 5 year period, there were a total of 221 pediatric firearm deaths, 285 firearm homicides and 29 firearm suicides. 2020 had a similar number of pediatric firearm homicides, 67, compared to prior years, range 47-82. The majority of these firearm homicides occurred in Black (76%) children aged 15-17 (74%). There were more firearm homicides in persons aged 1-14 (14) in 2020 compared to prior years (range 3-10). June and July 2020 saw the highest number of firearm homicides per month, 9 and 11. The months during Chicago's “stay at home” order did not see an increase in firearm homicides compared to prior years, 11 compared to range 0-19. 2020 had a greater number of pediatric firearm suicides, 11, compared to prior years, range 2-7. There were more firearm suicides in Black children in 2020, 5, compared to prior years, range 1-2. The majority of firearm suicides occurred in children aged 15-17 (73%). Additionally, 2020 saw more firearm suicides in children aged 10-14, 3, compared to prior years, range 0-2. The months during Chicago's “stay at home” order did not see an increase in firearm suicides compared to prior years, 0 compared to range 0-3. Conclusion: Firearm injuries are a leading cause of death in children. Changes in the epidemiology of pediatric firearm injuries during the 2020 COVID-19 pandemic in Chicago include a similar number of firearm homicides and an increased number of firearm suicides. Black male adolescents continue to be disproportionately affected by both firearm homicide and firearm suicide. There did not appear to be an increase in firearm homicides or firearm suicides during Chicago's “stay at home” order.

Transforming an Engineering Design Course into an Engaging Learning Experience Using a Series of Self-Directed Mini-Projects and ePortfolios: Face-to-Face Versus Online-only Instruction

Contemporary educational challenges have become amplified through the adoption of online-only modes of instruction due to the Covid-19 pandemic. When planning and delivering online instruction, even more than when delivering face-to-face instruction, engineering educators need to involve students at cognitive and emotional levels that encourage authentic, meaningful, and immersive learning experiences. During traditional online learning, students often feel disconnected from their learning communities. They also report a lack of motivation. Emotional engagement is therefore a necessary complement to cognitive engagement, while further helping to facilitate intrinsic motivation and feelings of delight, surprise, understanding, empathy, and trust. This study analyzes the use of scaffolded mini-projects (complex design projects divided into smaller segments) combined with comprehensive electronic portfolios (ePortfolios) in a sophomore-level Design for Manufacturability course. By emphasizing progressively more complex learning experiences and pairing these with electronic portfolios, students may become more attuned to cognitive learning processes such as effective planning and communication of complex ideas. We also hypothesize that they may develop awareness of, and competency in, skills with an emotional component including self-directed learning, autonomous exploration, and creative inspiration. For the purposes of this investigation, mini-projects may be independent from one another or connected as a series. Lessons from previous mini-projects are built into subsequent projects, and each offers loosely-defined analytical questions and open-ended design questions that require independent research. The unfolding of scaffolded mini-projects offers an orderly mechanism for students to grow and demonstrate important engineering competencies, especially when offered in tandem with teaching-learning-assessments via ePortfolios. ePortfolios have been shown to be effective in documenting learning competencies, enabling meta-analysis and personal reflection, and improving skills in the use of social media to communicate ideas. In effect, mini-projects combined with ePortfolios may help to facilitate deeper understanding of course content, make the curriculum more relevant for students, and build connections between classroom and professional learning competencies. This study offers a comparative analysis evaluating the efficacy of using mini-projects and ePortfolios in a face-to-face learning environment (Fall 2019) and in an online-only learning environment (Fall 2020). Participants in the face-to-face Fall 2019 (n = 104) course completed a questionnaire that evaluated specific engagement constructs. The completed questionnaires were evaluated using descriptive statistics and factor analysis. Data from the Fall 2020 (n = 64) course were evaluated using the same assessment methodology. It is hoped that findings from this work may contribute to the development of self-directed learning strategies that enhance students' cognitive and emotional engagement in their learning during online-only and face-to-face instruction. © American Society for Engineering Education, 2021

Anti-CD20 disease modifying therapies decrease the humoral response to COVID-19 mRNA vaccination in patients with multiple sclerosis

Introduction: B-cell depleting (anti-CD20) disease modifying therapies (DMT) for multiple sclerosis (MS) may increase the risk for COVID-19 and worsen clinical outcomes. How these patients respond to mRNA vaccines is not known since immunosuppressed patients were not included in clinical trials. Objective/Aim: To explore the humoral response in MS patients on B-cell depleting therapies to mRNA vaccination against COVID-19. Methods: Immunoglobulin G antibodies to the SARS-CoV-2 spike protein receptor binding domain (RBD) and nucleocapsid protein (N) were measured in MS patients and compared to control participants 3-4 weeks after initial and 3-6 weeks after the second mRNA vaccination. Clinical responses to the vaccination were also collected and compared. Results: After the 2nd vaccine dose, 10/10 controls developed antibodies to RBD, but only 2/10 MS patients on anti-CD20 DMTs (OR 0.014, 95% CI 0.0005 - 0.3328). After the 1st vaccine dose, 6/7 controls had seroconverted while 0/6 seroconverted in the anti- CD20 treated MS patients. Two patients who had COVID-19 on rituximab did not developed antibodies to the nucleocapsid protein but seroconverted to RBD after the 1st vaccination dose. Antibody titers were significantly reduced in the MS patients (p<0.001). No differences in clinical response to the vaccine were observed. T-cell responses are being evaluated and will be presented. Conclusions: Patients with MS on anti-CD20 DMT are less likely to develop antibodies to SARS-CoV-2 RBD and had lower titers after mRNA vaccination. This highlights the importance of better understanding vaccine responsiveness with larger studies and developing better strategies for effective vaccination in MS patients on B-cell depleting therapies.

Disparities in access to medical care after hospitalization for severe COVID-19 pneumonia

RATIONALE: Communities of color are bearing a disproportionate burden of coronavirus disease 2019 (COVID-19) morbidity and mortality. Social determinants of health have resulted in higher prevalence and severity of COVID-19 among minority groups. Published work on COVID-19 disparities has focused on higher transmission, hospitalization, and mortality risk among people of color, but studies on disparities in the post-acute care setting are scarce. Our aim was to identify socioeconomic disparities in health resource utilization after hospital discharge. METHODS: This was a retrospective study. We identified adult patients who were hospitalized at CUIMC or the Allen Hospital from March 1st through April 30th 2020, had a positive RT-PCR for severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), developed severe hypoxemic respiratory failure requiring invasive mechanical ventilation, and were successfully discharged from the hospital without need for ventilator support. Patients who received a tracheostomy and were weaned off the ventilator prior to discharge were included. Exclusion criteria included transfer from or to another institution, prior tracheostomy, in-hospital death, and discharge with a ventilator. RESULTS: We identified 195 patients meeting inclusion criteria. The median age was 59 (IQR 47-67), and 135 (66.5%) were men. There were 25 (12.8%) patients who were uninsured and 116 (59.5%) patients who had public insurance. There were 121 (62%) Hispanic, 34 (17%) Black, and 18 (9%) White patients. Uninsured patients within our cohort were more likely to be Hispanic and Spanish-speaking (p=0.027;p<0.001, respectively). Uninsured patients were also more likely to be discharged to home (p<0.001) than to a rehabilitation facility. 8.8% of patients were readmitted to CUIMC within 30 days and 41.5% saw a medical provider at CUIMC within 30 days of discharge. Insurance status did not predict 30-day re-hospitalization or completion of outpatient follow-up, although our study was underpowered to answer these questions. CONCLUSION: Our study demonstrated that race/ethnicity and primary language are associated with insurance status with Hispanic and Spanish-speaking patients being more likely to be uninsured. Uninsured patients were more likely to be discharged home after hospitalization, rather than to facility for further care and rehabilitation. We did not demonstrate any short-term differences in 30-day re-hospitalization rates or follow-up visits but we suspect socioeconomic disparities represent a significant barrier to adequate follow-up care in the long term. We plan to investigate this further with longitudinal follow-up and survey data.

Evaluation of patient satisfaction with an ophthalmology video consultation during the COVID-19 pandemic.

BACKGROUND: We introduced a video consultation (VC) during the coronavirus (COVID-19) pandemic in an ophthalmology practice with eight doctors to ensure continuous ophthalmological care, infection prophylaxis and to compensate a decreased number of patient presentations. OBJECTIVE: Evaluation of the most common reasons for patient presentations in the VC, the proportion of re-presentations in the practice despite VC, practical challenges associated with the introduction of VC and patient satisfaction. MATERIAL AND METHODS: Patients with a recent acute visual deterioration and severe eye pain were excluded from the VC. The VC were carried out by a trained specialist in ophthalmology. A questionnaire with eight questions was completed after the VC appointment in order to evaluate the proportion of completed VC and patient satisfaction. RESULTS: We included 29 (13 male, Ø 52.6 years, 16 female, Ø 64.7 years) patients in this analysis. The VC could be performed with 68.97% of the participants who rated their overall experience with an average grade of 1.6 (1 very good to 6 insufficient) and all of them indicated that they would recommend the VC. Of presentations in VC 70% were related to the symptoms of the anterior eye segment. In 70% of the cases no re-presentations took place in the unit. CONCLUSION: Our study represents a significant practical application of VC for the management of non-urgent ocular conditions with maximum infection prophylaxis. The introduction of VC was severely limited by technological or user-related issues by the establishment of video connections. Patient satisfaction with VC was high to very high.

[Evaluation of patient satisfaction with an ophthalmology video consultation during the COVID-19 pandemic]. / Evaluierung der Patientenzufriedenheit mit einer augenärztlichen Videosprechstunde während der COVID-19-Pandemie.

BACKGROUND: We introduced a video consultation (VC) during the coronavirus (COVID-19) pandemic in an ophthalmology practice with eight doctors to ensure continuous ophthalmological care, infection prophylaxis and to compensate a decreased number of patient presentations. OBJECTIVE: Evaluation of the most common reasons for patient presentations in the VC, the proportion of re-presentations in the practice despite VC, practical challenges associated with the introduction of VC and patient satisfaction. MATERIAL AND METHODS: Patients with a recent acute visual deterioration and severe eye pain were excluded from the VC. The VC were carried out by a trained specialist in ophthalmology. A questionnaire with eight questions was completed after the VC appointment in order to evaluate the proportion of completed VC and patient satisfaction. RESULTS: We included 29 (13 male, Ø 52.6 years, 16 female, Ø 64.7 years) patients in this analysis. The VC could be performed with 68.97% of the participants who rated their overall experience with an average grade of 1.6 (1 very good to 6 insufficient) and all of them indicated that they would recommend the VC. Of presentations in VC 70% were related to the symptoms of the anterior eye segment. In 70% of the cases no re-presentations took place in the unit. CONCLUSION: Our study represents a significant practical application of VC for the management of non-urgent ocular conditions with maximum infection prophylaxis. The introduction of VC was severely limited by technological or user-related issues by the establishment of video connections. Patient satisfaction with VC was high to very high.