Study of Clinical and Immune Severity Profiles of Patients Infected With SARS-Cov2 (COVID-19)

Study Overview
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Brief Summary
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The SARS-CoV2 virus causes severe or even fatal disease in a fraction of infected people. The clinical severity is based on a complicated pneumopathy with acute respiratory distress syndrome that can lead to multi-visceral failure. The underlying mechanism is a cytokinergic storm, an emerging facet of immunological dysregulation. This clinical trial is aimed to understand the mechanisms of this immunological dysregulation in order to identify therapeutic levers. The main objective is to understand the relationships between clinical severity, death or morbidity of resuscitation management, and immune status (i.e., immune pathways activated or not). Immune status will be investigated at many levels of organization (i.e., circulating leukocytes, cytokines and chemokines, transcripts). The secondary objectives are : to understand what is responsible for clinical severity, viral load, or immune activation; to highlight the consequences of immunological dysregulation on associated risks (i.e., immunosuppression leading to the emergence of infectious comorbidities) as well as the functioning of neurotransmission through metabolic pathway diversions. The impact of dysimmunity on these biological pathways will be assessed with a metabolomic analysis; to understand the mechanisms of vulnerability related to the field. Moreover, while co-morbidities are likely to be a risk factor for severe disease progression, there are many situations in which they do not occur. Stress, with its neurovegetative and endocrinological dimensions, modulates the immune response. It is essential to know whether the stress response plays a role in immunological dysregulation. This analysis is a prerequisite for understanding the conditions of treatment with glucocorticoids. Angiotensin converting enzyme type 2 (ACE2) also plays a likely role in host viral infection. It is also thought to play an important role in the emergence of severe syndromes by affecting the quality of vascular response.

Official Title
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Study of Clinical and Immune Severity Profiles of Patients Infected With SARS-Cov2

Conditions
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Respiratory Tract Infections, Respiratory Tract Disease

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient admitted to intensive care unit with confirmed SARS-CoV2 infection Patient older than 18 years old Exclusion Criteria: Patient coming from another intensive care unit after more than 5 days in the intensive care unit Known immunosuppression: Known or suspected HIV Known or suspected immunosuppression : Organ transplantation Marrow transplant Congenital deficit Received immunosuppressive therapy within 30 days (azathioprine, methotrexate, tacrolimus, cyclosporine, sirolimus, cyclophosphamide, rituximab, anti-TNF, JAK inhibitors, corticosteroids >10mg/day over the last 30 days, recent covid-19 corticosteroid therapy >1mg/kg prednisolone or equivalent >5 days) Administration of chemotherapy within the last 3 months Current pregnancy or breastfeeding Patient under 18 years of age Incapacitated adults and persons deprived of their liberty Refusal by the patient or his/her support person

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | Mortality | 90 days following the enrollment | 
| Immune response - Plasma cytokine profile | Th1/Th2/Th17/Treg balance, Type I Interferons and inflammation | Through study completion (90 days following the enrollment) | 
| Immune response - Phenotype of circulating cells | T cells (CD3, CD4, CD8, PD1, FAS, CD45RO, CTLA4+, CXCR5, CXCR3, CCR6, CD69, CD95, HLA-DR) and B cells (CD3, CD19, CD27, IgD, CD69) with cell subtypes and memory/naive compartments (CD27, CD38, IgD, IgG1, IgG2, IgG3, CD20, CD24), NK cells (CD14, CD16, CD56, HLA-DR), monocytes (CD14, CD45, HLA-DR, PDL-1) | Through study completion (90 days following the enrollment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Severity criteria - Duration of stay in intensive care unit | Number of days in intensive care unit | 90 days following the enrollment | 
| Severity criteria - Duration of hospitalization stay | Number of days of hospitalization | 90 days following the enrollment | 
| Severity criteria - Duration of period out of hospital | Number of days out of hospital | 90 days following the enrollment | 
| Severity criteria - Duration without mechanical ventilation | Number of days without mechanical ventilation (invasive/non-invasive) | 90 days following the enrollment | 
| Severity criteria - Duration without ventilation | Number of days not being ventilated | 90 days following the enrollment | 
| Severity criteria - Duration without intubation | Number of days not being intubated | 90 days following the enrollment | 
| Severity criteria - Number of transfusions | Number of transfusions | 90 days following the enrollment | 
| Severity criteria - Duration of the period without cathecholamines | Number of days without cathecholamines | 90 days following the enrollment | 
| Severity criteria - Duration of the period without dialysis | Number of days without dialysis | 90 days following the enrollment | 
| Severity criteria - SOFA | Sepsis-related Organ Failure Assessment (SOFA) Score | Through study completion (90 days following the enrollment) | 
| Severity criteria - LIS | Lung Injury Score (LIS) | Through study completion (90 days following the enrollment) | 
| SARS-Cov2 viral load | SARS-Cov2 viral load will be measured in blood and in broncho-tracheal secretions | Through study completion (90 days following the enrollment) | 
| Emergence of concomitant infections | Co-infections and acquired infections (bacterial or fungal) in intensive care unit, in particular based on an all-site positive PCR for EBV and/or CMV and/or HSV | 90 days following the enrollment | 
| Emergence of concomitant infections - Phenotype of circulating cells | T cells (CD3, CD4, CD8, PD1, FAS, CD45RO, CTLA4+, CXCR5, CXCR3, CCR6, CD69, CD95, HLA-DR) and B cells (CD3, CD19, CD27, IgD, CD69) with cell subtypes and memory/naive compartments (CD27, CD38, IgD, IgG1, IgG2, IgG3, CD20, CD24), NK cells (CD14, CD16, CD56, HLA-DR), monocytes (CD14, CD45, HLA-DR, PDL-1) | Through study completion (90 days following the enrollment) | 
| Stress physiological profile - Sympathetic tone | Heart rate variability | Through study completion (90 days following the enrollment) | 
| Stress physiological profile - Temperature | Core temperature | Through study completion (90 days following the enrollment) | 
| Stress physiological profile - Glucocorticoids | Quantity of glucocorticoids in the urine during 24 hours and at night | Through study completion (90 days following the enrollment) | 
| Angiotensin converting enzyme type II (ACE2) polymorphism - ACE | ACE Polymorphism | At enrollment | 
| Angiotensin converting enzyme type II (ACE2) polymorphism - ACE2/ACE1 | Protein expression of ACE2 vs. ACE1 and angiotensin II chain proteins | At enrollment | 
| Comorbidities - diabetes | Diabete diagnosis | At enrollment | 
| Comorbidities - Heart disease | Heart disease diagnosis | At enrollment | 
| Comorbidities - organ failure | Organ failure diagnosis | At enrollment | 
| Plasma concentrations of several metabolic pathways - GABA | GABA level in blood and urine | Through study completion (90 days following the enrollment) | 
| Plasma concentrations of several metabolic pathways - Glucocorticoid | Glucocorticoid level in blood and urine | Through study completion (90 days following the enrollment) | 
| Plasma concentrations of several metabolic pathways - Tryptophan | Tryptophan in blood and urine | Through study completion (90 days following the enrollment) | 
| Plasma concentrations of several metabolic pathways - Serotonin | Serotonin level in blood and urine | Through study completion (90 days following the enrollment) | 
| Plasma concentrations of several metabolic pathways - Dopamin | Dopamin level in blood and urine | Through study completion (90 days following the enrollment) | 
| Plasma concentrations of several metabolic pathways - Cathecholamines | Catecholamines level in blood and urine | Through study completion (90 days following the enrollment) | 
| Plasma concentrations of several metabolic pathways - Arachidonic acid derivatives | Arachidonic acid derivatives level in blood and urine | Through study completion (90 days following the enrollment) | 
| Plasma concentrations of several metabolic pathways - Endocannabinoids | Endocannabinoids level in blood and urine | Through study completion (90 days following the enrollment) |