RA-COVID-19 V17 - Recherche - Action Coronavirus disease 2019 - Vague 17

Characterization of the microVAScular dysfunction in COvid-19 ARDS. – VASCO

VASCOV Exploration of microVascular involvement of COVID-19 ARDS

Endothelial damage and coagulation activation at the lung microvascular level may play an important role in the physiopathology of the COVID-19 ARDS. The project aims to prospectively investigate both bedside pulmonary physiological markers (mainly alveolar dead-space) and biological markers of coagulopathy and endothelial dysfunction in COVID-19 and non-COVID-19 ARDS patients.

To establish that the alveolar dead space is significantly higher in patients with COVID-19 ARDS, compared to patients with non-COVID-19 ARDS.

To establish the prognostic value of the alveolar-dead space (measured iteratively) in patients with COVID-19 and non-COVID-19 ARDS.<br />Establish the respective influences of the biological parameters of endothelial damage, of the biological parameters of coagulopathy, of the parameters set on the artificial ventilator on the value of the alveolar dead space; in patients with COVID-19 and non-COVID-19 ARDS.<br />To establish the prognostic value of the laboratory parameters of endothelial damage and coagulopathy in patients with COVID-19 and non-COVID-19 ARDS.<br />Secondary evaluation criteria:<br />• Physiological dead space<br />• Circulating endothelial cells<br />• D-dimers<br />• Willebrand factor: antigenic value, activity, multimeric profile<br />• Components of the fibrinolytic system (plasma and bronchoalveolar lavage fluid)<br />• Components of NETs (Neutrophil Extracellular Traps) (plasma and bronchoalveolar lavage fluid)<br />• Fragments of the proteins of interest cleaved by elastase (plasma and bronchoalveolar lavage fluid)<br />• E-selectin, endoglin, VEGF-A, VEGFR-2, Angiopoietin -1 and -2, cKit and SDF-1<br />• Soluble protein C endothelial receptor (sEPCR)<br />• SARS-CoV-2 viremia (ARDS COVID-19)<br />• Parameters set on the artificial respirator<br />• Respiratory mechanics parameters<br />• Gas exchange parameters<br />• Survival at D90<br />• Duration of respiratory assistance<br />• Length of stay (in intensive care, hospitalization)

Selection visit: between 1 hour and at the latest 2 days before the inclusion visit.
Research follow-up visits:
The 1st follow-up visit (D0) of the research will take place within 24 hours of inclusion
The following visits (D1, D2, D3,…, Dx) will take place throughout the duration of invasive mechanical ventilation:
• SAPSII and SOFA clinical severity scores: D0 only
• Living / deceased status
• Status: patient under invasive mechanical ventilation: yes / no
For patients under invasive mechanical ventilation and up to D28 after inclusion:
• Clinical examination: blood pressure, heart and respiratory rates, body temperature,
• Respiratory assistance parameters
• Sedation and analgesia scores (RASS, BPS)
• Arterial gas measurement
• ECG
• Data recording of the artificial respirator for measuring the alveolar dead space
• Biological blood test as part of the study: carried out on D0 then every 3 +/- 1 days:
o Circulating endothelial cells (CEC)
o D-dimers
o Willebrand factor
o Components of the fibrinolytic system
o Components of NETs (Neutrophil Extracellular Traps
o Fragments of the proteins of interest cleaved by elastase
o Endothelial proteomics
o SARS-CoV-2 viremia (ARDS linked to COVID-19) by digital PCR in microdroplets
o Absolute quantification of the pulmonary specific circulating methylation marker (ARDS linked to COVID-19 or not linked to COVID-19) by digital microdroplet PCR
o Samples for assays (components of the fibrinolytic system, components of NETs, ??fragments of the proteins of interest cleaved by elastase) on bronchoalveolar lavage fluid: on the day of the examination

End of research visit at D90
o Living / deceased status
o If deceased: Date of death
o Number of days under invasive mechanical ventilation after inclusion
o Number of days under invasive mechanical ventilation after admission to intensive care
o Day (s) of the tracheal extubation (s)
o Day (s) of possible tracheal reintubation (s)
o Duration of hospitalization in intensive care
o Total hospital stay

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Endothelial damage and coagulation activation at the lung microvascular level may play an important role in the physiopathology of the COVID-19 ARDS. The project aims to prospectively investigate both bedside pulmonary physiological markers (mainly alveolar dead-space) and biological markers of coagulopathy and endothelial dysfunction in COVID-19 and non-COVID-19 ARDS patients.
In December 2019, an outbreak of pneumonia caused by a new coronavirus occurred in Wuhan and spread rapidly throughout China, with an evolution towards a global pandemic. Originally called new coronavirus 2019 (2019-nCoV), the virus was later officially named Coronavirus 2 of Severe Acute Respiratory Syndrome (SARS-CoV-2) by WHO. On 30 January 2020, WHO declared the SARS-CoV-2 outbreak as a public health emergency of international concern. Compared to SARS-CoV, which caused an outbreak of SARS in 2003, SARS-CoV-2 has a higher transmission capacity. The clinical manifestations of severe forms of SARS-CoV-2 are dominated by respiratory symptoms, leading in the more severe cases to Acute Respiratory Distress syndrome (ARDS). Understanding the impairments caused by SARS-CoV-2 to the respiratory and vascular systems and the underlying mechanisms is of an utmost importance.
A coagulopathy is found in severe cases of SARS-CoV-2 infection, including significantly higher levels of D-dimers in severe forms and fatalities as compared to survivors. Accordingly, the hypothesis of microthrombosis at the organ level was first proposed for renal injury. High levels of creatinine were associated with higher levels of D-Dimers, which could suggest a micro-thrombotic origin for kidney failure. Thereafter, pulmonary thrombotic complications were reported both at the pulmonary arterial level and at the rich capillary lung level. Endothelial dysfunction (triggered by endothelial cells viral infection) and its microthrombotic consequences may thus play a major role in the respiratory physiopathologic process. Indeed, the SARS-CoV-2 receptor (ACE2) is strongly expressed in lung cells, preferentially alveolar type II cells, but also lung endothelial cells. Infection of endothelial cells could cause a lesion of the endothelium but also an activation that can trigger the activation of coagulation.
Circulating endothelial cells (CECs) are markers of severe endothelial lesions and may act as non-invasive markers of pulmonary vascular dysfunction during SARS-CoV-2 infection, beside other biological markers of endothelial dysfunction. CECs are defined by a number of phenotypic and functional morphological criteria, which differentiate them from endothelial progenitor cells. Physiological bedside respiratory markers, such as physiological dead-space and more importantly alveolar dead-space, extracted from the advanced pulmonary monitoring performed in ARDS patients, could be highly correlated to such markers. Accordingly, the translational project proposes to study different aspects of the underlying pathophysiology of SARS-CoV-2 ARDS and to support specific therapeutic approaches.
We propose to fully study in SARS-CoV-2 ARDS patients: (i) bedside pulmonary physiological parameters during the ICU clinical course, with alveolar dead-space as a major study parameter (ii) coagulation and fibrinolytic systems and (iii) endothelium activation and senescence. This work will contribute to a better description of the SARS-CoV-2 ARDS pathophysiology and should allow identifying patients' profile in which curative anticoagulant therapy or even thrombolytic treatments could be considered. Additionally, specific mechanical ventilator settings could also be proposed.

Project coordination

Jean-Luc Diehl (Jean-Luc Diehl)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

PRIME Jean-Luc Diehl
NANOMEDECINE REGENERATIVE
IThEM INNOVATIONS THERAPEUTIQUES EN HEMOSTASE
CRC CENTRE DE RECHERCHE DES CORDELIERS
PARCC PARIS CENTRE DE RECHERCHE CARDIOVASCULAIRE

Help of the ANR 155,024 euros
Beginning and duration of the scientific project: February 2021 - 12 Months

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