Evaluation of Interleukine 6 (and Other Cytokines and Inflammatory Markers) in COVID-19 Patients With a Systemic Inflammatory Response Syndrome

Evaluation of Interleukine 6 (and Other Cytokines and Inflammatory Markers) in SARS-Cov-2 Infected Patients With a Systemic Inflammatory Response Syndrome

In patients infected by the SARS-Cov-2 Coronavirus a severely progressive disease requiring hospitalization in intensive care seems related to deregulation of cytokines with very high levels of IL-6, IL-2, IL-7, IL-10 and TNF-α. In order to elucidate the mechanism of this hyper inflammatory syndrome we will measure a panel of pro and anti inflammatory cytokines, as well as known markers of macrophage activation syndrome.

To determine the role of activation of the complement cascade the most important complement factors and their activation markers will be measured.

The changes of those parameters will be monitored after administration of an anti-IL6R antibody therapy.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Diagnostic test: Cytokines dosage; Diagnostic test: Complement dosage

Detailed Description

In patients with severely progressive SARS-Cov-2 Coronavirus infection, the elderly and immunocompromised are at greater risk of progressing to a serious image of ARDS (Acute Respiratory Distress syndrome). A recent study has shown that patients, sometimes young, requiring hospitalization in intensive care have deregulation of cytokines with very high levels of IL-6, IL-2, IL-7, IL-10 and TNF-α. The cytokines involved in the pathogenesis and clinical manifestations of CRS are mainly IL-6, gamma interferon (IFN-g), tumor necrosis factor alpha (TNF-a) and IL-10.

Although immunoinflammatory therapy is not systematically recommended in pneumonia linked to SARS-CoV-2, given the CRS and the pathophysiological results of pulmonary edema and the formation of the hyaline membrane, a targeted therapeutic approach and temporally accompanied by adequate ventilatory support could be beneficial in patients with severe pneumonia who develop ARDS. Tocilizumab (Roactemra®) is a drug that blocks the IL-6 receptor commonly prescribed for the treatment of rheumatoid arthritis. The intravenous formulation has been approved for the treatment of CRS which occurs during treatment with Car-T; given the clinical picture and cytokine levels in patients with severe SARS-Cov-2 pneumonia, Tocilizumab or another anti-IL6R antagonist may reasonably be expected to contribute to the control of virus-induced Systemic Inflammatory Response Syndrome (SIRS) in patients with elevated levels of IL-6.

The objectivation of high interleukin 6 levels in these patients should be an important scientific argument to justify the administration of therapy based on antagonization of IL6. Measurement of other pro inflammatory cytokines will shed light on the mechanism of the inflammatory syndrome induced by the SARS-CoV-2 virus.

One of the pathophysiological mechanisms of pulmonary pathology could be the induction of the production of complement factors by interleukin 6 as well as the activation of the complement cascade by the virus via the lectin pathway. It is known that one of the effects of Tocilizumab is to reduce the concentration of the various complement factors, the synthesis of which is under the control of interleukin 6. This is why this study proposes to measure certain parameters of the complement (CH50, C3, C4, C3d, C5a, SC5b-9, C4a, MASP-2) in order to objectify and quantify this activation.

If the activation of the complement proves significant it could be an argument for a treatment targeting more specifically the cascade of the complement.

• Study Type: Interventional
• Enrollment (Actual): 63
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1020
    • CHU Brugmann

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• End of the initial phase of high viral load of SARS-Cov-2 (for example apyretic> 72h and / or at least 7 days after the onset of symptoms)
• Worsening of respiratory exchanges which require non-invasive or invasive ventilation support (BCRSS score ≥3)
• High levels of IL-6 (> 40 pg / ml); alternatively high levels of d-dimer and / or PCR and / or ferritin and / or fibrinogen gradually increase.
• A control group will be formed by patients in the Covid unit who do not have respiratory problems justifying a transfer to intensive care.

Exclusion Criteria:

• Documented sepsis caused by other pathogens other than SARS-Corv-2.
• Presence of comorbidities likely to lead, according to clinical judgment, to an unfavorable result
• Immunosuppressive anti-rejection therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ventilation support; The experimental group will include Covid-19 infected patients with non-invasive or invasive ventilation support (BCRSS score ≥3).	Diagnostic test: Cytokines dosage; Dosage of inflammatory cytokines and other markers of systemic inflammatory syndromes (TNFa, IFNg, IL1, IL7, IL10, IL12, IL17, sCD25, sCD163, sCD14, IL-6, IL6-R, complex IL6-IL6R, glycolsylated ferritin...).; Diagnostic test: Complement dosage; Dosage of the complement parameters: CH50, C3, C4, C3d, C5a, SC5b-9, C4a, MASP-2.
Other: Control group; The control group will include Covid-19 infected patients who don't have respiratory problems justifying a transfer to intensive care.	Diagnostic test: Cytokines dosage; Dosage of inflammatory cytokines and other markers of systemic inflammatory syndromes (TNFa, IFNg, IL1, IL7, IL10, IL12, IL17, sCD25, sCD163, sCD14, IL-6, IL6-R, complex IL6-IL6R, glycolsylated ferritin...).; Diagnostic test: Complement dosage; Dosage of the complement parameters: CH50, C3, C4, C3d, C5a, SC5b-9, C4a, MASP-2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IL6 concentration	Interleukine 6, soluble IL6-R, complex IL6-IL6R concentration	Before anti-IL6R treatment (baseline)
IL6 concentration change from baseline value	Interleukine 6 soluble IL6-R, complex IL6-IL6R variation compared to baseline value	Twice a week from day 1 to day 14 post anti-IL6R administration
Complement parameters	CH50, C3, C4, C3d, C5a, SC5b-9, C4a, MASP-2	Before anti-IL6R treatment (baseline)
Complement parameters change from baseline values	CH50, C3, C4, C3d, C5a, SC5b-9, C4a, MASP-2 variation compared to baseline values	Twice a week from day 1 to day 14 post anti-IL6R administration
Inflammatory cytokines baseline concentrations	Concentration of TNFa, IFNg, IL1, IL7, IL10, IL12, IL17, IL18	Before anti-IL6R treatment (baseline)
Inflammatory cytokines change from baseline values	Concentration of TNFa, IFNg, IL1, IL7, IL10, IL12, IL17, IL18 variation compared to baseline values	Twice a week from day 1 to day 14 post anti-IL6R administration

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Concentration of markers of macrophage activation	sCD25, sCD163, sCD14, glycosylated ferritin	Before anti-IL6R treatment (baseline)
Markers of macrophage activation change from baseline values	sCD25, sCD163, sCD14, glycosylated ferritin variation compared to baseline values	Twice a week from day 1 to day 14 post anti-IL6R administration

Collaborators and Investigators

• Sponsor: Francis Corazza

Publications and helpful links

General Publications

• Ponthieux F, Dauby N, Maillart E, Fils JF, Smet J, Claus M, Besse-Hammer T, Bels D, Corazza F, Nagant C. Tocilizumab-Induced Unexpected Increase of Several Inflammatory Cytokines in Critically Ill COVID-19 Patients: The Anti-Inflammatory Side of IL-6. Viral Immunol. 2022 Jan-Feb;35(1):60-70. doi: 10.1089/vim.2021.0111. Epub 2022 Jan 27.

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2020
• Primary Completion (Actual): November 23, 2020
• Study Completion (Actual): November 23, 2020

Study Registration Dates

• First Submitted: April 13, 2020
• First Submitted That Met QC Criteria: April 13, 2020
• First Posted (Actual): April 15, 2020

Study Record Updates

• Last Update Posted (Actual): September 29, 2021
• Last Update Submitted That Met QC Criteria: September 28, 2021
• Last Verified: September 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Inflammation; Shock; COVID-19; Systemic Inflammatory Response Syndrome; Physiological Effects of Drugs; Immunologic Factors; Complement System Proteins
• Other Study ID Numbers: CHUB-IL6-COVID-19

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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