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

• Conditions: Respiratory Tract Infections; Respiratory Tract Disease

• Registration Number: NCT04365166
• Lead Sponsor: Direction Centrale du Service de Santé des Armées

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2020-04-19
• Study Start: 2020-04-21
• Study First Submitted QC: 2020-04-24
• Study First Posted: 2020-04-28
• Status Verified: 2021-03
• Last Update Submitted: 2021-03-08
• Last Update Posted: 2021-03-09
• Primary Completion: 2022-04-21
• Study Completion: 2022-04-21

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 100

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 & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Immune response - Phenotype of circulating cells	Through study completion (90 days following the enrollment)	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)
Immune response - Plasma cytokine profile	Through study completion (90 days following the enrollment)	Th1/Th2/Th17/Treg balance, Type I Interferons and inflammation
Mortality	90 days following the enrollment	Mortality

Secondary Outcome Measures

Name	Time	Method
Severity criteria - Duration without mechanical ventilation	90 days following the enrollment	Number of days without mechanical ventilation (invasive/non-invasive)
Emergence of concomitant infections	90 days following the enrollment	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
Angiotensin converting enzyme type II (ACE2) polymorphism - ACE	At enrollment	ACE Polymorphism
Plasma concentrations of several metabolic pathways - Arachidonic acid derivatives	Through study completion (90 days following the enrollment)	Arachidonic acid derivatives level in blood and urine
Plasma concentrations of several metabolic pathways - Glucocorticoid	Through study completion (90 days following the enrollment)	Glucocorticoid level in blood and urine
Plasma concentrations of several metabolic pathways - Cathecholamines	Through study completion (90 days following the enrollment)	Catecholamines level in blood and urine
Severity criteria - Duration of period out of hospital	90 days following the enrollment	Number of days out of hospital
Severity criteria - Duration of the period without cathecholamines	90 days following the enrollment	Number of days without cathecholamines
Severity criteria - Duration of the period without dialysis	90 days following the enrollment	Number of days without dialysis
Severity criteria - SOFA	Through study completion (90 days following the enrollment)	Sepsis-related Organ Failure Assessment (SOFA) Score
SARS-Cov2 viral load	Through study completion (90 days following the enrollment)	SARS-Cov2 viral load will be measured in blood and in broncho-tracheal secretions
Stress physiological profile - Sympathetic tone	Through study completion (90 days following the enrollment)	Heart rate variability
Stress physiological profile - Temperature	Through study completion (90 days following the enrollment)	Core temperature
Stress physiological profile - Glucocorticoids	Through study completion (90 days following the enrollment)	Quantity of glucocorticoids in the urine during 24 hours and at night
Severity criteria - Duration of stay in intensive care unit	90 days following the enrollment	Number of days in intensive care unit
Severity criteria - Number of transfusions	90 days following the enrollment	Number of transfusions
Severity criteria - LIS	Through study completion (90 days following the enrollment)	Lung Injury Score (LIS)
Emergence of concomitant infections - Phenotype of circulating cells	Through study completion (90 days following the enrollment)	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)
Angiotensin converting enzyme type II (ACE2) polymorphism - ACE2/ACE1	At enrollment	Protein expression of ACE2 vs. ACE1 and angiotensin II chain proteins
Plasma concentrations of several metabolic pathways - Tryptophan	Through study completion (90 days following the enrollment)	Tryptophan in blood and urine
Plasma concentrations of several metabolic pathways - Serotonin	Through study completion (90 days following the enrollment)	Serotonin level in blood and urine
Severity criteria - Duration of hospitalization stay	90 days following the enrollment	Number of days of hospitalization
Comorbidities - Heart disease	At enrollment	Heart disease diagnosis
Plasma concentrations of several metabolic pathways - GABA	Through study completion (90 days following the enrollment)	GABA level in blood and urine
Plasma concentrations of several metabolic pathways - Dopamin	Through study completion (90 days following the enrollment)	Dopamin level in blood and urine
Severity criteria - Duration without ventilation	90 days following the enrollment	Number of days not being ventilated
Severity criteria - Duration without intubation	90 days following the enrollment	Number of days not being intubated
Comorbidities - diabetes	At enrollment	Diabete diagnosis
Comorbidities - organ failure	At enrollment	Organ failure diagnosis
Plasma concentrations of several metabolic pathways - Endocannabinoids	Through study completion (90 days following the enrollment)	Endocannabinoids level in blood and urine

Trial Locations

Locations (2)

Percy Military Teaching Hospital; 🇫🇷 Clamart, France

Bégin Military Teaching Hospital; 🇫🇷 Saint-Mandé, France