COVID-19 is responsible of a pandemic since December 31 2019, which began in China and
spread rapidly. Confirmed Covid positive patients worlwide is estimated at 179 M in June
2021. The infection started in France at the beginning of 2020 and causes severe
pneumonia with 130,519 confirmed cases, including 2,712 (2.1%) hospitalizations in
intensive care units. COVID-19 emerges as a poorly understood systemic disease that
affects several organs, especially the lungs. The first reason for worsening and
hospitalization in intensive care is acute respiratory distress syndrome (ARDS) that
requires heavy and long care management with orotracheal intubation and mechanical
ventilation, as well as prolonged sedation and curarization. Patients who survived this
critical phase should then be weaned from this invasive monitoring as quickly as possible
to limit risk of morbidity and mortality. It therefore appears essential to do everything
possible to reduce the duration of mechanical ventilation and the period of ventilatory
weaning, a real daily challenge in intensive care, for both medical and socio-economic
sides.

Beside COVID-19 infection, the ventilatory weaning phase is a long and difficult period
that can last more than 40 to 60% of the time spent under mechanical ventilation and can
be more complicated as the duration of sedation is prolonged. This phase is correlated
with the duration of mechanical ventilation, as well as with respiratory, cardiac and
neuromuscular diseases. Considering all the risk factors for prolonged ventilatory
weaning, one of these is the intensive care delirium.

Delirium in intensive care is a serious event, possibly leading to mortality or acute and
late complications (self-extubation, catheter removal, ...) since 30% of delirium
patients develop cognitive sequelae. The incidence of this post-ARDS delirium is
approximately 20% according to the studies and is found predominantly in patients with
severe sepsis. The academic tool to access delirium in intensive care is the CAM-ICU
(Confusion Assessment Mehod - ICU) scale; the RASS score (Richmond Agitation-Sedation
Scale) is also usable to access patients with a hyperactive form (RASS score greater than
2).

Several drug strategies based on the use of sedating agents such as dexmedetomidine or
certain neuroleptics such as loxapine or haloperidol have been developed to reduce this
incidence. Dexmedetomidine is a selective adrenergic receptor agonist and has hypnotic
and analgesic properties.

At the same time, dexmedetomidine exhibits neuroprotective effects. In experimental
models such as intraperitoneal injection of lipopolysaccharide or LPS, marrow lesions or
ischemia-reperfusion models, dexmedetomidine reduces cerebral inflammation with a direct
action on the microglial phenotype. The impacted signaling pathway is still unclear,
however several studies show an action of dexmedetomidine on the AMPK pathway. The use of
dexmedetomidine to prevent and treat delirium is not uniform within intensive care units
in France and is not administered systematically.

Unexpectedly, two thirds of patients hospitalized in intensive care for ARDS after
COVID-19 infection develop a severe delirium. This unique incidence is double the
incidences found in other populations in ICU (sepsis, meningitis,...).

Neuroinflammation reaction induced by an intra or extra-cranial phenomenon is a very
studied process.

The latter is totally correlated with the strength of the stimulus and can be the cause
of a disturbance or a complete runaway of the immune system described in the literature
as an inflammatory storm. This neuroinflammation induced during the IC hospitalization is
now known to persist, until several years after outbreak.

The role of this chronic neuroinflammatory persistent response on cognitive capacities
and reserve begins to emerge in the literature regardless of the initial stress (surgery,
head trauma, or Alzheimer-type dementia) and is therefore capable of influencing the
quality of life of patients. The evaluation of this neuroinflammation using non-invasive
tools appears to be essential in the management of cerebrolesed patients.

Among existing tools, positron emission tomography (PET) imaging using radiotracers
specific for monocytic/microglial activation is now recognized as a relevant tool because
of its sensitive and specific characteristics to assess brain inflammation. Several
radiotracers have been tested, in particular [11C] -PK11195, but it is [18F] -DPA-714 or
DPA that is retained in the literature because it has many pharmacokinetic advantages. He
has indeed shown his interest in a few animal and human models in various pathologies. It
should be noted that the DPA receptor exhibits a polymorphism that may explain certain
differences in binding observed in humans. This tool, by means of a quantitative and
possibly regional measurement of the signal measurement, is particularly innovative and
seems to correlate with cognitive disorders, particularly in the context of Alzheimer's
disease. Currently, the technology combining MRI and PET imaging with DPA appears to be
the most successful for evaluating neuroinflammation, allowing regional measurement with
better resolution. Recent studies have also been able to show that the increase in DPA by
PET-MRI was associated with a pejorative cognitive evolution.

The role of peripheral inflammation on the neuro-inflammatory profile is now well
described with both mediation via cytokines / chemokines produced by systemic immunity
but also by infiltration and cellular exchanges of the monocyte / macrophage cells, which
interact directly with the microglia. Although the full range of mechanisms is still
poorly understood, it seems that there is a very close communication between the
peripheral immune system and the central nervous system, causing an initial inflammatory
runaway. Thus, it seems opportune in our cohort for which neuroinflammation is suspected,
to combine the quantification of the main circulating mediators (cytokine and chemokine
assays) and cellular (PBMC cell sorting [Peripheral blood mononuclear cells], with
transcriptomic and epigenomic analysis as well as proteomics with time-of-flight
cytometry or Cytof) easily accessible in the blood of patients in order to best describe
in a minimally invasive manner this inflammatory reaction and to be able propose a
follow-up and a potential therapeutic strategy.