Clinical trial NCT04386395: Immune Changes in Severe COVID-19 Pulmonary Infections
Official title: Whole Blood Immune Cells Characterization in Critically Ill COVID-19 Patients: A Prospective Study
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: SARS-CoV-2
Immune System Disorder
Lead sponsor: Central Hospital, Nancy, France
Sponsor class: OTHER
First posted: 2020-05-13
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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

Brief 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.

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.

Eligibility criteria: Inclusion Criteria: confirmed COVID-19

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

Exclusion Criteria:

* none

Primary outcomes:
measure: Changes in monocytes HLA-DR expression
timeFrame: through ICU stay, an average of 30 days
measure: Changes in lymphocytes subpopulations numbers
timeFrame: through ICU stay, an average of 30 days
measure: Changes in monocytes number
timeFrame: through ICU stay, an average of 30 days
Secondary outcomes:
measure: TNFalpha level
timeFrame: 4 hours
measure: INFgamma level
timeFrame: 4 hours
measure: IL1beta level
timeFrame: 4 hours
measure: SOFA score
timeFrame: through ICU stay, an average of 30 days
measure: number of recorded deaths
timeFrame: through study completion, an average of 6 months
measure: presence of pneumonia
timeFrame: through ICU stay, an average of 30 days
measure: presence of bacteremia
timeFrame: through ICU stay, an average of 30 days
measure: presence of urinary tract infection
timeFrame: through ICU stay, an average of 30 days
measure: C reactive protein
timeFrame: through ICU stay, an average of 30 days
measure: D Dimers
timeFrame: through ICU stay, an average of 30 days
Other outcomes:
Locations:
city: Vandoeuvre-les-Nancy
country: France
facility: Centre Hospitalier Universitaire NANCY
Study officials:
affiliation: Central Hospital, Nancy, France
name: MARIE REINE LOSSER, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
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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.