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Understanding Immunology and Patient Outcomes of COVID-19 in Hospitalized Patients

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ClinicalTrials.gov Identifier: NCT04892797
Recruitment Status : Recruiting
First Posted : May 19, 2021
Last Update Posted : May 19, 2021
Sponsor:
Information provided by (Responsible Party):
Renee Stapleton, University of Vermont

Brief Summary:

The adaptive immune response, consisting of antiviral T and B cells, is critical for providing protection against viruses such as SARS-CoV-2, both during an active infection and later following a subsequent exposure. They can both also potentially contribute to pathogenesis if they are overstimulated. Despite these advances in knowledge, there are still significant gaps in our understanding of what constitutes a protective or immunopathologic immune response and its durability.

Significant knowledge gaps also remain pertaining to the early recognition of COVID patients with increased risk of clinical deterioration who require continued hospitalization and the use of more intensive treatments designed to improve outcomes. Data from non-COVID patients with MI show that platelet surface expression of FcγRIIa, the low-affinity receptor for the Fc fragment of immunoglobulin (Ig) G, identifies patients at high and low risk of subsequent cardiovascular events. Platelet expression of FcγRIIa is increased by interferon γ20 that is significantly elevated in severe COVID-19 infections. The high prevalence of arterial thrombosis among COVID-19 patients and the central role of thrombosis in respiratory failure support our hypothesis that elevated platelet expression of FcγRIIa will identify COVID patients at increased risk of thrombotic complications and clinical deterioration.

In addition to the potential role of platelet activation in thrombosis associated with COIVD-19, the endothelium may also play a significant role. The investigators hypothesize that elevated EMPs in plasma will identify patients at high risk of thrombosis and clinical deterioration.

To begin to address the knowledge gaps above and obtain preliminary data for future large grant submission, the investigators propose a small, prospective, single-center cohort study that will enroll patients hospitalized for COVID-19 infection and exhibiting a range of disease severity. Biosamples will be obtained and used to study T and B cells, antibody repertoire, and durability of protective immunity, and also to quantify platelet expression of FcγRIIa and circulating EMPs, as described in the protocol.


Condition or disease Intervention/treatment
Covid19 Other: Covid-19+ observational

Detailed Description:

Since December 2019, the novel coronavirus (SARS-CoV-2) and associated COVID-19 illness has spread worldwide. Globally, there are >86 million infections and over 1.8 million confirmed deaths, with the pandemic continuing at record levels throughout the USA. While new data on COVID-19 are emerging daily, several knowledge gaps remain, including our understanding of the adaptive immune response to infection, the propensity for infected patients to experience thrombotic events, and identification of biomarkers that might predict clinical deterioration.

The adaptive immune response, consisting of antiviral T and B cells, is critical for providing protection against viruses such as SARS-CoV-2, both during an active infection and later following a subsequent exposure. They can both also potentially contribute to pathogenesis if they are overstimulated. Much has been learned about the T and B cell responses to SARS-CoV-2 since the beginning of the COVID-19 pandemic. The most comprehensive study to date shows that most individuals make a balanced T and B cell response that persists for at least 8 months. Despite these advances in knowledge, there are still significant gaps in our understanding of what constitutes a protective or immunopathologic immune response and their durability.

Significant knowledge gaps also remain pertaining to the early recognition of COVID patients with increased risk of clinical deterioration who require continued hospitalization and the use of more intensive treatments designed to improve outcomes. In addition, the identification of low risk patients who can be discharged from the hospital would reduce the use of potentially scarce medical resources, particularly during a surge. Among patients with thrombosis, 49% required critical care and 43% died. Data from non-COVID patients with MI show that platelet surface expression of FcγRIIa, the low-affinity receptor for the Fc fragment of immunoglobulin (Ig) G, identifies patients at high and low risk of subsequent cardiovascular events. Platelet expression of FcγRIIa is increased by interferon γ20 that is significantly elevated in severe COVID-19 infections. Because FcγRIIa amplifies platelet activation, greater expression of FcγRIIa on the surface of the platelet increases platelet reactivity. The high prevalence of arterial thrombosis among COVID-19 patients and the central role of thrombosis in respiratory failure support the hypothesis that elevated platelet expression of FcγRIIa will identify COVID patients at increased risk of thrombotic complications and clinical deterioration.

In addition to the potential role of platelet activation in thrombosis associated with COIVD-19, the endothelium may also play a significant role. The endothelium is a key site of entry for COVID-19 infection and endothelial injury contributes to thrombotic events that increase morbidity and mortality. Endothelial microparticles (EMPs), submicron membranous vesicles indicating endothelial activation and injury, are released by the endothelium into blood and reflect the competency of endothelial function by identifying endothelial activation and injury, which promote thrombosis. Circulating EMPs can be quantified with the use of flow cytometry. We hypothesize that elevated EMPs in plasma will identify patients at high risk of thrombosis and clinical deterioration.

To begin to address the knowledge gaps above and obtain preliminary data for future large grant submission, the investigators propose a small, prospective, single-center cohort study that will enroll patients hospitalized for COVID-19 infection and exhibiting a range of disease severity. Blood will be obtained on study days 1, 3±1, 7±1 (and every 7±1 days thereafter up to day 28 while hospitalized), and again at 12 months of follow up. Nasopharyngeal (NP) swabs will be collected on these same study days through day 28, but not at 12 months. These biosamples will be used to study T and B cells, antibody repertoire, and durability of protective immunity, and also to quantify platelet expression of FcγRIIa and circulating EMPs, as described in the protocol.

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Study Type : Observational
Estimated Enrollment : 60 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Understanding Immunology and Patient Outcomes of COVID-19: A 1-Year Longitudinal Follow-Up Study of Hospitalized Patients
Actual Study Start Date : February 3, 2021
Estimated Primary Completion Date : February 2, 2022
Estimated Study Completion Date : February 2, 2023

Group/Cohort Intervention/treatment
Covid-19+
Hospitalized patients with Covid-19 infection confirmed by PCR test
Other: Covid-19+ observational
This is observational--there is no intervention




Primary Outcome Measures :
  1. To compare the polyfunctionality and frequency of antiviral CD4 and CD8 T cells. [ Time Frame: Four weeks (while hospitalized) ]
    We hypothesize patients with severe disease will have higher frequencies of antiviral T cells that contribute to the cytokine storm observed in the most severe cases of COVID-19.

  2. To compare the polyfunctionality and frequency of antiviral CD4 and CD8 T cells. [ Time Frame: 12 months after hospital admission ]
    We hypothesize patients with severe disease will have higher frequencies of antiviral T cells that contribute to the cytokine storm observed in the most severe cases of COVID-19.

  3. To compare the frequency of plasmablasts (early B cells that produce antiviral antibodies) and plasma antiviral antibody titer during acute infection. [ Time Frame: Four weeks (while hospitalized) ]
    We predict that patients with severe disease will have greater numbers of antiviral plasmablasts and plasma antiviral antibody levels compared to those with mild disease.

  4. To compare the frequency of plasmablasts (early B cells that produce antiviral antibodies) and plasma antiviral antibody titer during acute infection. [ Time Frame: 12 months after hospital admission ]
    We predict that patients with severe disease will have greater numbers of antiviral plasmablasts and plasma antiviral antibody levels compared to those with mild disease.

  5. The number of virus specific CD4 T cells will be measured using flow cytometry. [ Time Frame: Four weeks (while hospitalized) ]
    We hypothesize that severe disease will result in the formation of higher magnitude antiviral B and T cell CHRMS (Medical) #STUDY00001369 Approved: 1/25/2021 4Human subjects protocol form 7/19/19responses during acute disease due to increased viral load and antigen in these patients. We further predict that higher frequency T and B cells during acute disease will correlate with more robust durability of these responses during convalescence.

  6. The number of virus specific CD8 T cells will be measured using flow cytometry. [ Time Frame: Four weeks (while hospitalized) ]
    We hypothesize that severe disease will result in the formation of higher magnitude antiviral B and T cell CHRMS (Medical) #STUDY00001369 Approved: 1/25/2021 4Human subjects protocol form 7/19/19responses during acute disease due to increased viral load and antigen in these patients. We further predict that higher frequency T and B cells during acute disease will correlate with more robust durability of these responses during convalescence.

  7. The number of virus specific CD4 T cells will be measured using flow cytometry. [ Time Frame: 12 months after hospital admission ]
    We hypothesize that severe disease will result in the formation of higher magnitude antiviral B and T cell CHRMS (Medical) #STUDY00001369 Approved: 1/25/2021 4 Human subjects protocol form 7/19/19 responses during acute disease due to increased viral load and antigen in these patients. We further predict that higher frequency T and B cells during acute disease will correlate with more robust durability of these responses during convalescence.

  8. The number of virus specific CD8 T cells will be measured using flow cytometry. [ Time Frame: 12 months after hospital admission ]
    We hypothesize that severe disease will result in the formation of higher magnitude antiviral B and T cell CHRMS (Medical) #STUDY00001369 Approved: 1/25/2021 4Human subjects protocol form 7/19/19responses during acute disease due to increased viral load and antigen in these patients. We further predict that higher frequency T and B cells during acute disease will correlate with more robust durability of these responses during convalescence.

  9. To obtain preliminary data on platelet activation in patients hospitalized with COVID-19 [ Time Frame: Four weeks (while hospitalized) ]
    To compare platelet activation, measured by platelet surface FcγRIIa while in hospital and 12 months after infection, in patients with severe (i.e., mechanical ventilation in ICU) vs. non-severe (hospitalized, but not in an ICU) COVID-19 disease.

  10. To obtain preliminary data on platelet activation in patients hospitalized with COVID-19 [ Time Frame: 12 months after hospital admission ]
    To compare platelet activation, measured by platelet surface FcγRIIa while in hospital and 12 months after infection, in patients with severe (i.e., mechanical ventilation in ICU) vs. non-severe (hospitalized, but not in an ICU) COVID-19 disease.

  11. To obtain preliminary data on endothelial activation in patients hospitalized with COVID-19 [ Time Frame: Four weeks (while hospitalized) ]
    To compare endothelial activation, measured by circulating EMPs while in hospital and 12 months after infection, in patients with severe (i.e., mechanical ventilation in ICU) vs. non-severe (hospitalized, but not in an ICU) COVID-19 disease.

  12. To obtain preliminary data on endothelial activation in patients hospitalized with COVID-19 [ Time Frame: 12 months after hospital admission ]
    To compare endothelial activation, measured by circulating EMPs while in hospital and 12 months after infection, in patients with severe (i.e., mechanical ventilation in ICU) vs. non-severe (hospitalized, but not in an ICU) COVID-19 disease.

  13. Preliminarily determine if the FcγRIIa and EMPs have utility as biomarkers [ Time Frame: Four weeks (while hospitalized) ]
    To preliminarily determine if the FcγRIIa and EMPs have utility as biomarkers for prediction of thrombotic events and clinical deterioration in hospitalized patients with COVID-19.

  14. Preliminarily determine if the FcγRIIa and EMPs have utility as biomarkers [ Time Frame: 12 months after hospital admission ]
    To preliminarily determine if the FcγRIIa and EMPs have utility as biomarkers for prediction of thrombotic events and clinical deterioration in hospitalized patients with COVID-19.


Biospecimen Retention:   Samples With DNA
blood, nasal swabs


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
This study will enroll patients hospitalized at the University of Vermont Medical Center who have a positive test result for COVID-19. These patients are expected to have a greater acuity of illness and burden of disease based on the fact that they require inpatient care. Enrolling hospitalized patients ensures a greater opportunity to collect serial biological specimens over the course of the illness due to the proximity of the patient to medical and research staff and UVM laboratories.
Criteria

Inclusion Criteria:

  1. Adult (≥18 years old) at the time of consent
  2. Positive COVID-19 PCR test result

Exclusion Criteria:

  1. Expected death or withdrawal of life-sustaining treatments within 3 days
  2. Hemoglobin ≤7.0 at the time of consent
  3. Unable to provide consent and no legally authorized representative (LAR) identified or reached by phone
  4. Pregnant
  5. Incarcerated
  6. Physician declines patient enrollment (attending physician or study physician)
  7. Patient or LAR do not consent to participate in the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04892797


Contacts
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Contact: Renee Stapleton, MD, PhD 802-656-7975 renee.stapleton@med.uvm.edu
Contact: Sara Ardren, PA 802-656-7953 sara.ardren@med.uvm.edu

Locations
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United States, Vermont
University of Vermont Recruiting
Burlington, Vermont, United States, 05405
Contact: Sara Ardren, PA    802-656-7953    sara.ardren@med.uvm.edu   
Principal Investigator: Renee Stapleton, MD, PhD         
Sub-Investigator: MaryEllen Ankowiak, MD         
Sponsors and Collaborators
University of Vermont
Investigators
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Principal Investigator: Renee Stapleton, MD, PhD University of Vermont
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Responsible Party: Renee Stapleton, Professor of Medicine, University of Vermont
ClinicalTrials.gov Identifier: NCT04892797    
Other Study ID Numbers: 00001369
First Posted: May 19, 2021    Key Record Dates
Last Update Posted: May 19, 2021
Last Verified: April 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No