Immune Changes in Severe COVID-19 Pulmonary Infections (COVIDIMM)

Whole Blood Immune Cells Characterization in Critically Ill COVID-19 Patients: A Prospective Study

SARS-CoV-2 outbreak causes a spectrum of clinical patterns that varies from asymptomatic infection to mildly symptomatic manifestations and more-severe forms that need intensive care. Until now, the immune response to SARS-CoV-2 virus infection has been poorly reported to help decision for immune modulation therapies. As a consequence, trials have been designed to test both anti-inflammatory molecules as steroids or anti-bodies against IL-6, and others proposing to "boost" immunity with interferon beta based on similar inclusion criteria.

The immune response to infective agents including viruses may have a complex time evolution with early and late phases corresponding to different patterns, oscillating between pro-inflammation and immune-depression. The potential window to improve outcome in COVID-19 by therapeutic intervention aimed at a fine tuning between immune toxicity and immunodepression requires a longitudinal assessment during the course of illness, especially for the patients who develop acute respiratory failure. Immune monitoring of both innate and adaptive immunity would then be essential to appropriately design clinical trials.

The whole blood cells evaluation was recorded according to the time intervals between the onset of symptoms and the sampling after ICU admission. Patients' care was standardized, especially with regard to ventilation, sedation, and antimicrobial treatment.

In this study the investigators prospectively perform a longitudinal study of both innate and adaptive immunity on patients admitted to ICU for an COVID-19 related acute respiratory failure. The data will be analyzed in reference to the onset of initial symptoms and also to the admission in ICU.

The primary end point is the evolution of the characterization of monocytes and their subsets in term of number and expression of HLA-DR. A similar approach is used for lymphocytes and their subtypes with in addition, an ex vivo testing of their capabilities to be stimulated by SARS-CoV-2 viral proteins in term of TNFalpha, INFgamma, and IL1beta production.

The secondary end-point was to test the association with outcomes and other non-specific markers of inflammation as CRP (C reactive protein), PCT (procalcitonin), DDimers and ferritin.

Study Overview

• Status: Completed
• Conditions: SARS-CoV-2; Immune System Disorder

Detailed Description

The most severe form of COVID-19 treated in intensive care for acute respiratory failure may have a poor prognosis. Both the level of IL-6 and the severity of the lymphopenia have been associated to the poor prognosis. Better knowledge of the time evolution of the circulating immune cells subpopulations and functions will help to best tailor the treatment: anti-inflammatory strategy at the initial phase might be rapidly shifted to immune stimulation when immunodepression is diagnosed.

It is then essential to assess the patients' immune status using flowcytometry methods to characterize both innate and adaptive immunity of the whole blood circulating immune peripheral blood mononuclear cells (PBMC). After cell staining with the adequate cell markers, the flowcytometry (NAVIOS® Flow Cytometer (Beckman Coulter) allowed to analyze the number and the function of the cells with an adequate gating strategy and the Kaluza® software v2.1 (Beckman Coulter). The data were then grouped by time intervals referring to the onset of symptoms and also to the ICU admission. The trend for innate immunity (monocytes number and subpopulations, HLA-DR expression) and for adaptive immunity (lymphocytes and subpopulations) will be analyzed. Since it is unknown if whole blood CD3/CD4 and CD3/CD8 lymphocytes elicit an "exhaustion" pattern and/or an abnormal response, an ex vivo testing of their reactivity for SARS-CoV-2 viral proteins will be performed. This test of polyfunctionality will characterize the intracellular cytokine expression (IL-1 beta, TNFalpha, and INFgamma) both for CD4 and CD8 T cells.

• Study Type: Observational
• Enrollment (Actual): 50

Contacts and Locations

Study Locations

• France
  • Vandoeuvre-les-Nancy, France, 54511
    • Centre Hospitalier Universitaire Nancy

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

COVID-19 ICU patients, sedated and mechanically ventilated within the 48 hrs of admission for the first sampling, and monitored all over their ICU stay

Description

Inclusion Criteria: confirmed COVID-19

• a positive RT- PCR,
• a highly suggestive thoracic CTScan,
• severe hypoxemia

Exclusion Criteria:

• none

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
Immuno Cohort; COVID-19 confirmed ICU patients, sedated and ventilated, sequential characterization of circulating immune cells over their ICU stay. Every 2 to 3 days, fresh whole blood aliquots from routine blood counts were processed on a Flow Cytometer (Beckman Coulter) to determine immune cells subpopulations
Cortico Cohort; COVID-19 confirmed ICU patients, sedated and ventilated, sequential characterization of circulating immune cells over their ICU stay. According to RECOVERY study, early routine administration of dexamethasone 6 mg/day over 10 days. Every 2 to 3 days, fresh whole blood aliquots from routine blood counts were processed on a Flow Cytometer (Beckman Coulter) to determine immune cells subpopulations

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in monocytes HLA-DR expression	circulating immune cell characterization	through ICU stay, an average of 30 days
Changes in lymphocytes subpopulations numbers	circulating immune cell characterization	through ICU stay, an average of 30 days
Changes in monocytes number	circulating immune cell characterization	through ICU stay, an average of 30 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
TNFalpha level	stimulation by SARS-CoV-2 viral proteins	4 hours
INFgamma level	stimulation by SARS-CoV-2 viral proteins	4 hours
IL1beta level	stimulation by SARS-CoV-2 viral proteins	4 hours
SOFA score	Sequential Organ dysfunction assessement, ranging from 0 (better) to 24 (worst) outcome	through ICU stay, an average of 30 days
number of recorded deaths	mortality	through study completion, an average of 6 months
presence of pneumonia	infectious complications	through ICU stay, an average of 30 days
presence of bacteremia	infectious complications	through ICU stay, an average of 30 days
presence of urinary tract infection	infectious complications	through ICU stay, an average of 30 days
C reactive protein	inflammation marker	through ICU stay, an average of 30 days
D Dimers	inflammation marker	through ICU stay, an average of 30 days

Collaborators and Investigators

• Sponsor: Central Hospital, Nancy, France
• Investigators: Principal Investigator: MARIE REINE LOSSER, MD, PhD, Central Hospital, Nancy, France

Publications and helpful links

General Publications

• Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN, Leenen PJ, Liu YJ, MacPherson G, Randolph GJ, Scherberich J, Schmitz J, Shortman K, Sozzani S, Strobl H, Zembala M, Austyn JM, Lutz MB. Nomenclature of monocytes and dendritic cells in blood. Blood. 2010 Oct 21;116(16):e74-80. doi: 10.1182/blood-2010-02-258558. Epub 2010 Jul 13.
• Tan L, Wang Q, Zhang D, Ding J, Huang Q, Tang YQ, Wang Q, Miao H. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Signal Transduct Target Ther. 2020 Mar 27;5(1):33. doi: 10.1038/s41392-020-0148-4. No abstract available. Erratum In: Signal Transduct Target Ther. 2020 Apr 29;5(1):61.
• Hotchkiss RS, Monneret G, Payen D. Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy. Nat Rev Immunol. 2013 Dec;13(12):862-74. doi: 10.1038/nri3552. Epub 2013 Nov 15.
• Payen D, Faivre V, Miatello J, Leentjens J, Brumpt C, Tissieres P, Dupuis C, Pickkers P, Lukaszewicz AC. Multicentric experience with interferon gamma therapy in sepsis induced immunosuppression. A case series. BMC Infect Dis. 2019 Nov 5;19(1):931. doi: 10.1186/s12879-019-4526-x.
• Alattar R, Ibrahim TBH, Shaar SH, Abdalla S, Shukri K, Daghfal JN, Khatib MY, Aboukamar M, Abukhattab M, Alsoub HA, Almaslamani MA, Omrani AS. Tocilizumab for the treatment of severe coronavirus disease 2019. J Med Virol. 2020 Oct;92(10):2042-2049. doi: 10.1002/jmv.25964. Epub 2020 May 10.
• Payen D, Cravat M, Maadadi H, Didelot C, Prosic L, Dupuis C, Losser MR, De Carvalho Bittencourt M. A Longitudinal Study of Immune Cells in Severe COVID-19 Patients. Front Immunol. 2020 Oct 23;11:580250. doi: 10.3389/fimmu.2020.580250. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (Actual): March 30, 2020
• Primary Completion (Actual): May 30, 2020
• Study Completion (Actual): June 30, 2021

Study Registration Dates

• First Submitted: May 6, 2020
• First Submitted That Met QC Criteria: May 12, 2020
• First Posted (Actual): May 13, 2020

Study Record Updates

• Last Update Posted (Actual): July 15, 2021
• Last Update Submitted That Met QC Criteria: July 9, 2021
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases
• Other Study ID Numbers: CHRU NANCY : 2020PI080_1

Drug and device information, study documents

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