Systematic Assessment of SARS-CoV-2 Neurotropic Capacity in Modestly and Critically Ill Patients, and Patients Who Died From COVID-19

COVID-19 Disease Clinical Trial

Official title:

Systematic Assessment of SARS-CoV-2 Neurotropic Capacity in Modestly and Critically Ill Patients, and Patients Who Died From COVID-19

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04472013
• Other study ID #: 2020-01503; ch20Hutter
• Status: Completed
• Start date: August 12, 2020
• Est. completion date: November 9, 2022

Study information

• Verified date: November 2022
• Source: University Hospital, Basel, Switzerland
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

This study is to analyze the microglia reaction or direct neurotropic effects of CNS COVID-19 in pathogenesis and brain stem dysfunction in critically ill patients. A microglia-focused, brain-specific 50+ marker CODEX panel is used to assess the neuroinflammatory microenvironment in specific brain regions of deceased COVID-19 patients. The peripheral (cerebrospinal fluid and peripheral blood) cytokine response to SARS-CoV-2 is investigated in regard to CNS affection and consecutive blood brain barrier disruption leading to braininherent neuroinflammatory reactions

Description:

This study is to analyze the microglia reaction or direct neurotropic effects of CNS COVID-19 in pathogenesis and brain stem dysfunction in critically ill patients. A microglia-focused, brain-specific 50+ marker CODEX panel is used to assess the neuroinflammatory microenvironment in specific brain regions of deceased COVID-19 patients. The peripheral (cerebrospinal fluid and peripheral blood) cytokine response to SARS-CoV-2 is investigated in regard to CNS affection and consecutive blood brain barrier disruption leading to braininherent neuroinflammatory reactions. Primary endpoints of this project are the multidimensional integration of the analysis from the procedures described above and assessment of the correlation between the gained clinical data (MRI, mental/neurological state), the body fluid proteomic and mass-cytometric analysis (CSF and Plasma proteomics, peripheral blood mass cytometry) and the CODEX analysis of defined brain regions on autopsy specimens.

Non-critically ill COVID-19 patients and critically ill COVID-19 patients needing mechanical ventilation at the ICU are included. Autopsy specimens from medulla oblongata, cortex, cerebellum and olfactory bulb are investigated, including only tissue samples, which have been submitted to the Institute of Pathology, University Hospital Basel.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: November 9, 2022
• Est. primary completion date: November 9, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• COVID-19 positive tested

Exclusion Criteria:

• COVID-19 negative tested

• pregnant women

Related Conditions & MeSH terms

• COVID-19
• COVID-19 Disease

Intervention

Other:
• Data collection from lumbar puncture
Cerebro spinal fluid (CSF) will be acquired by lumbar puncture and sent for routine analysis including CSF chemistry, cytology and microbiology. Targeted CSF proteomics using OLINK Proximity Extension Assay (PEA) technology to assess a potential CNS-contribution of the disease will be performed.
• Data collection from blood draw
Plasma samples will be acquired for plasma cytokine proteomics using CyTOF (mass cytometry analysis) technology.
• CNS magnetic resonance imaging (MRI) imaging
3Tesla magnetic resonance imaging (MRI) will be performed to document early/manifest encephalitic changes in COVID-19 patients.
• Microscopy of defined brain regions on autopsy specimens
High dimensional, microglia-centric CODEX fluorescent microscopy of defined brain regions on autopsy specimens will be acquired from medulla oblongata, cortex, cerebellum, and olfactory bulb. A brain-specific CODEX panel for the assessment of the immune microenvironment was implemented, with inclusion of a wide array of myeloid/microglia markers, T-cell markers, and a few neuronal markers. All the antibodies have been validated and tested in formalin-fixed tissues of different zones of glioblastoma tumors including invading tumor periphery. The Panel will be modified to include the viral entry receptors, CD147, ACE2 and TMPRSS2. Presence of SARS-CoV-2 virus particles will be assessed by qPCR, andMultiplexed Ion Beam Imaging (MIBI) technology will be used to visualize tropism of virus to specific cellular brain compartments.

Locations

Country	Name	City	State
Switzerland	Neurosurgery, University Hospital Basel	Basel

Sponsors (2)

Lead Sponsor	Collaborator
University Hospital, Basel, Switzerland	Botnar Research Centre for Child Health

Country where clinical trial is conducted

Switzerland, 

References & Publications (1)

Etter MM, Martins TA, Kulsvehagen L, Pössnecker E, Duchemin W, Hogan S, Sanabria-Diaz G, Müller J, Chiappini A, Rychen J, Eberhard N, Guzman R, Mariani L, Melie-Garcia L, Keller E, Jelcic I, Pargger H, Siegemund M, Kuhle J, Oechtering J, Eich C, Tzankov A, Matter MS, Uzun S, Yaldizli Ö, Lieb JM, Psychogios MN, Leuzinger K, Hirsch HH, Granziera C, Pröbstel AK, Hutter G. Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study. Nat Commun. 2022 Nov 9;13(1):6777. doi: 10.1038/s41467-022-34068-0. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	MRI imaging data	Comparison of lesions from patients that are neurologically affected to non-affected individuals in terms of CNS involvement to describe encephalitic changes due to COVID-19 infection.	Project duration for each patient takes 1 hour for the MRI at baseline
Primary	Proteomic analysis	Description of proteomic biomarkers (CSF and Plasma) in comparison with control reference sample.	10 minutes for blood draw at baseline
Primary	Peripheral blood leukocyte Cytof Mass Cytometry Analysis for cell population frequency	Mass cytometry will be performed form peripheral blood mononuclear cells to count cell population frequency.	10 minutes for blood draw at baseline
Primary	CODEX (high dimensional microscopy) workflow analysis of defined regions on brain autopsy specimens	In situ distribution assessment of marker expression (CD147 protein, ACE2 protein, Transmembrane protease serine subtype 2 (TMPRSS2))	at baseline

External Links

•   Severe Neuro-COVID is associated with peripheral immune signatures, autoimmunity and neurodegeneration: a prospective cross-sectional study