Calprotectin, a Biomarker of COVID-19 Severity (CALPRO)

Study Overview
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Brief Summary
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The purpose of this study is to provide new insights into the pathophysiology of emergency hematopoiesis detected in severe COVID-19 patients. The investigators aim to explore the ability of calprotectin to induce an immunosuppressive myeloid program at the hematopoietic stem and progenitor cell (HSPC) level, and to identify the receptor(s) involved in this effect. Since patients with a hematological malignancy demonstrate a very high propensity to develop a severe COVID-19, the investigators will explore how HSPCs collected from patients with a myeloid malignancy respond to calprotectin.

Detailed Description
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Emergency myelopoiesis in response to SARS-CoV-2 infection produce immunosuppressive myeloid cells with accumulation of immature granulocytes and loss of non-classical monocytes. Excessive release of calprotectin, the dimer of S100A8/A9 alarmins, by immature granulocytes and activated monocytes reflects this situation. A role of calprotectin has been previously described in the initiation and progression of chronic hematological malignancies such as myelodysplastic syndromes. To provide a rationale for the targeting of alarmin-driven signaling pathways and limit the pathogenic inflammatory response to SARS-CoV-2 infection, the role of calprotectin in the production of immunosuppressive cells from the bone marrow hematopoietic stem and progenitors cells needs to be investigated in patients with severe COVID-19 in comparison with patients with chronic myeloid malignancies (such as chronic myelomonocytic leukemia and myelodysplastic syndromes) and with age-mached healthy controls. A comprehensive and integrated multiomics approach will be used to decipher the features of immunosuppressive cells and identify therapeutic targets in deregulated pathways.

Official Title
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Calprotectin Involvement in Emergency Hematopoiesis Observed in Severe COVID-19

Conditions
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Severe/Moderate Coronavirus, Chronic Myelomonocytic Leukemia, Myelodysplastic Syndromes, Old Age

Intervention / Treatment
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* Biological: Blood samples


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Criteria for all groups: Adults ≥ 18 years Dated and signed inform consent * * : written informed consent of relative (trusted person, close family) in case of emergency procedure, by default emergency inclusion notified in medical file and pursuance consent sought. Affiliation with a social security scheme Criteria for control group: Age-matched healthy donors Criteria for chronic myeloid malignancies: A diagnosis of low or high-risk myelodysplastic syndromes according to the WHO 2016 classification A diagnosis of dysplastic or proliferative chronic myelomonocytic leukemia according to WHO 2016 Criteria for COVID-19 patients: Patients with a recent diagnosis (<7 days since first symptoms) of moderate or severe COVID-19 Exclusion Criteria: Pregnant women Minor patient or major under protection Patients with COVID-19 infection and active cancer or a history of cancer within the last 6 months Patients with COVID-19 and severe comorbidities including cardiovascular or respiratory diseases, unbalanced diabetes, obesity (IMC >29) Patient on AME (state medical aid)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: COVID-19 patients (group 1)<br>Patients with a recent diagnosis (<7 days since first symptoms) of moderate or severe COVID-19 | Biological: Blood samples<br>* blood<br>|
| Experimental: Chronic myeloid malignancies (group 2)<br>Adults with chronic myeloid malignancies including myelodysplastic syndromes with low risk MDS ; high risk MDS according to IPSS-R or with dysplastic or proliferative chronic myelomonocytic leukemia according to WHO2016 | Biological: Blood samples<br>* blood<br>|
| Other: Control group (group 3)<br>Age-matched healthy donors | Biological: Blood samples<br>* blood<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Differential gene expression and epigenetic signature of COVID-19 or leukemic versus normal HSC using CITE-seq and ATAC-seq | Hematopoietic stem and progenitor cells from patients with severe or moderate COVID-19 or chronic myeloid malignancies or controls will be purified for analyses of transcriptome and chromatin conformation, and also functionally characterized using in vitro culture systems. Results will be compared between the three groups. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ex vivo testing of calprotectin-receptor interaction inhibitor | Expression of targeted receptors will be monitored by flow cytometry. Clinically developed compounds that could inhibit calprotectin effects will be tested in vitro. | During the last 6 months of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Calprotectin, hematopoiesis, COVID-19