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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Respiratory Tract Infections; Respiratory Tract Disease

• Study Type: Observational
• Enrollment (Anticipated): 100

Contacts and Locations

• Study Contact: Name: Nicolas LIBERT, MD, PhD; Phone Number: +33 141466772; Email: nicolas.libert@intradef.gouv.fr

Study Locations

• France
  • Clamart, France, 92140
    • Recruiting
    • Percy Military Teaching Hospital
    • Contact: Nicolas LIBERT, MD, PhD; Phone Number: +33 141466772; Email: nicolas.libert@intradef.gouv.fr
  • Saint-Mandé, France, 94163
    • Not yet recruiting
    • Bégin Military Teaching Hospital
    • Contact: Clément DUBOST, MD, PhD; Phone Number: +33 143985048; Email: clement.dubost@intradef.gouv.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

The target population is a population infected with SARS-CoV2 and justifying hospitalisation in an intensive care unit, i.e. presenting at least one immediate vital failure that would lead in short term to the death of the patient without the implementation of an adapted active therapeutic intervention. As the variable of interest is immuno-inflammatory activation, patients with an immune deficiency of any origin will be excluded. Patients will be recruited from patients admitted to the intensive care unit with biological confirmation of SARS-Cov2 infection.

Description

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

Study Plan

How is the study designed?

What is the study measuring?

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)

Collaborators and Investigators

• Sponsor: Direction Centrale du Service de Santé des Armées

Study record dates

Study Major Dates

• Study Start (Actual): April 21, 2020
• Primary Completion (Anticipated): April 21, 2022
• Study Completion (Anticipated): April 21, 2022

Study Registration Dates

• First Submitted: April 19, 2020
• First Submitted That Met QC Criteria: April 24, 2020
• First Posted (Actual): April 28, 2020

Study Record Updates

• Last Update Posted (Actual): March 9, 2021
• Last Update Submitted That Met QC Criteria: March 8, 2021
• Last Verified: March 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Respiratory Tract Infections; Respiratory Tract Diseases
• Other Study ID Numbers: 2020-COVID19-05; 2020-A00898-31 (Other Identifier: IDRCB)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No