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Immunophenotyping  the Hospitalized COVID-19 Patient Immunophenotyping  the Hospitalized COVID-19 Patient

Immunophenotyping the Hospitalized COVID-19 Patient - PowerPoint Presentation

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Immunophenotyping the Hospitalized COVID-19 Patient - PPT Presentation

Presented by Scott Brakenridge MD Associate Professor of Surgery amp Anesthesiology UF Sepsis amp Critical Illness Research Center ScottBrakenridgesurgeryufledu Brakenridgemd The immune response to COVID19 is characterized by ID: 909914

covid immune adaptive cell immune covid cell adaptive elispot patients immunosuppression response brakenridge cells functional host results data cytokine

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Presentation Transcript

Slide1

Immunophenotyping

the Hospitalized COVID-19 Patient

Presented by:

Scott Brakenridge, MD

Associate Professor of Surgery & Anesthesiology

UF Sepsis & Critical Illness Research Center

Scott.Brakenridge@surgery.ufl.edu

@

Brakenridge_md

Slide2

The immune response to COVID-19 is characterized by…(???)

Current pathophysiologic dogma and therapeutic approach to COVID-19 has focused on viral replication (

Remdesivir

) and blunting the initial host “cytokine storm” (

sarilumab

, tocilizumab).Emerging trial results →

Interacting on these mechanisms

Ø effective…

However, emerging data suggests after the initial inflammatory response, immune suppression predominates and predicts mortality.

Severe

lymphopenia

& T-cell exhaustion

Immunosuppression

co-exists with

and/or follows the initial inflammatory responseSignificant heterogeneity is present in other acute host innate immune responses (i.e., Sepsis, severe trauma)Understanding the immunologic trajectory and “endotypes” of COVID-19 infection is key for mechanistic selection and design of COVID clinical trials.

(Remy, Brakenridge et al; Commentary -

Lancet

Resp

Med

2020)

Slide3

Innovation/Rationale

All current enrolling or proposed COVID-19 interventional trials utilizing

immunomodulating

agents focus on attempting to blunt the initial “cytokine storm” which in current dogma is thought to drive the severe pulmonary clinical manifestations of the disease. However,

both the immunologic trajectory of the host immune response remains incompletely defined

. We propose to characterize both the magnitude and trajectory of the host immune response, and define the impact of lymphopenia and immunosuppression on patient outcomes.

Most if

not all of the current biomarkers proposed are static phenotypic markers of either inflammatory or immune status. What we propose here is a

functional measure of the dynamic status of both cells of the innate and

adaptive

immune system In COVID-19 patients over time

. We believe that the phenotype of the cell, either from cell surface expression, proteomics or

transcriptomics

, will be less informative than measuring the ex vivo capability of cells to respond to exogenous ligand stimulation

.Enzyme-linked immune absorbent spot (ELISpot) is a highly sensitive immunoassay that measures the frequency of cytokine-secreting cells at the single-cell level 12. In addition to detecting the number of cytokine secreting cells, the relative amount of cytokine produced by each cell can be determined by quantitating the area of each spot. Importantly, ELISpot is technically easy to perform, more sensitive at revealing group differences in cell function compared to other methods, and can independently assess the functional status of both innate and adaptive immunity. ELISpot results are readily obtained overnight, and there are existing CAP-CLIA laboratories that are using this assay for testing adaptive immune responses to M. tuberculosis and Candida infections (e.g., Oxford LLP, Quest Diagnostics). Therefore, we can take advantage moving forward of an existing infrastructure to rapidly translate these results into CAP-CLIA-accredited, FDA-cleared diagnostic assays.

We

have shown that myeloid derived suppressor cells (MDSC) play a significant role in persistent immunosuppression in critically ill surgical patients with sepsis. COVID-19 patients exhibit profound and deadly immunosuppression, thought to be due mainly to T-cell exhaustion.

We propose that expansion of myeloid suppressor cell (MDSC) populations contribute significantly to this immune suppression and represent a valid therapeutic target

.

Slide4

Project Aims

To characterize both the magnitude and trajectory of the host immune response, and define the impact of

lymphopenia

and immunosuppression on COVID-19 patient outcomes.

To determine the time course of adaptive immune suppression during disease progression and resolution or death, focusing on blood T cell production of

IFN-g

and stimulated monocyte production of

TNF-a

as quantitated by a novel functional bioassay (ELISpot).

To determine whether expansion of myeloid-derived suppressor cells (MDSC) contributes to the adaptive immune failure seen in COVID-19 infected patients..

Slide5

Project Design

2-Center prospective observational cohort study (UF/

WashU

)

Established collaborators, 2 synergistic & independently (CTSI) funded studies

30 COVID-19, 30 bacterial sepsis, 15 healthy controls (same at WashU)

Serial biologic sample acquisition

Peripheral blood

Pulmonary aspirate/secretions (became logistically problematic…)

Analyses

Serial immune biomarkers (IL-6, IL-8, IL-10, sPD-L1)

Ex vivo

immune functional phenotyping (ELISpot)

T-cell/MDSC phenotyping and suppression analyses (Flow cytometry & functional assays)

Slide6

Enzyme-Linked Immune absorbent Spot (ELISpot)

Practical, timely, dynamic and functional measure of both

innate and adaptive

immunity

A

ssessment of cellular response (spot count) and function (spot size)

Facilitates rapid testing of

ex vivo response to therapeutics

Existing CAP-CLIA laboratory application for tuberculosis and fungal infections

(S. Brakenridge

preliminary data

)

Slide7

Progress/Preliminary Results

Severe/progressive adaptive immune

suppresion

Ex vivo

IL-7 ‘rescue’

Enrollment

26 COVID patients, 11 sepsis patients, 7 healthy controls

Samples banked for pooled biomarker/genomic analyses

Ongoing ELISpot analyses

ELISpot adaptive immunity accruing data

Slide8

Progress/Preliminary Results

WashU

preliminary data

Consistent findings of profound adaptive immunosuppression

Slide9

Summary

CTSI funded pilot project nearing completion

Preliminary data already accruing

There is evidence of profound adaptive immunosuppression in COVID-19 patients

ELISpot exhibits the potential for rapid translation to clinical relevant diagnostics

Immune stimulants may offer efficacy in restoring immunosuppression in COVID-19 patients

UF investigators (Brakenridge/Moldawer) are multi-center study leads in recently initiated international COVID-19 IL-7 clinical trial