Immune Changes in Severe COVID-19 Pulmonary Infections

SARS-CoV-2 Clinical Trial

— COVIDIMM  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04386395
• Other study ID #: CHRU NANCY : 2020PI080_1
• Status: Completed
• Start date: March 30, 2020
• Est. completion date: June 30, 2021

Study information

• Verified date: December 2020
• Source: Central Hospital, Nancy, France
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 50
• Est. completion date: June 30, 2021
• Est. primary completion date: May 30, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria: confirmed COVID-19

• a positive RT- PCR,

• a highly suggestive thoracic CTScan,

• severe hypoxemia

Exclusion Criteria:

• none

Related Conditions & MeSH terms

• Immune System Diseases
• Immune System Disorder
• SARS-CoV-2

Locations

Country	Name	City	State
France	Centre Hospitalier Universitaire NANCY	Vandoeuvre-les-Nancy

Sponsors (1)

Lead Sponsor	Collaborator
Central Hospital, Nancy, France

Country where clinical trial is conducted

France, 

References & Publications (6)

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. — View Citation

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. Review. — View Citation

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. — View Citation

Payen D, Faivre V, Miatello J, Leentjens J, Brumpt C, Tissières 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. — View Citation

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. Erratum in: Signal Transduct Target Ther. 2020 Apr 29;5(1):61. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in monocytes HLA-DR expression	circulating immune cell characterization	through ICU stay, an average of 30 days
Primary	Changes in lymphocytes subpopulations numbers	circulating immune cell characterization	through ICU stay, an average of 30 days
Primary	Changes in monocytes number	circulating immune cell characterization	through ICU stay, an average of 30 days
Secondary	TNFalpha level	stimulation by SARS-CoV-2 viral proteins	4 hours
Secondary	INFgamma level	stimulation by SARS-CoV-2 viral proteins	4 hours
Secondary	IL1beta level	stimulation by SARS-CoV-2 viral proteins	4 hours
Secondary	SOFA score	Sequential Organ dysfunction assessement, ranging from 0 (better) to 24 (worst) outcome	through ICU stay, an average of 30 days
Secondary	number of recorded deaths	mortality	through study completion, an average of 6 months
Secondary	presence of pneumonia	infectious complications	through ICU stay, an average of 30 days
Secondary	presence of bacteremia	infectious complications	through ICU stay, an average of 30 days
Secondary	presence of urinary tract infection	infectious complications	through ICU stay, an average of 30 days
Secondary	C reactive protein	inflammation marker	through ICU stay, an average of 30 days
Secondary	D Dimers	inflammation marker	through ICU stay, an average of 30 days