Humanity is experiencing since November 2019 a new pandemic by the novel SARS Coronavirus-19
(SARS-CoV-2). As of March 16 2020 170,191 documented case were reported worldwide of which
6,526 died1. The analysis of the clinical characteristics of these patients showed that among
those who were critically ill with acute respiratory failure the risk of death was as high as
60%2. Main clinical feature is the presence of comorbidities and age more than 60 years
whereas main laboratory findings are leukopenia and lymphopenia with hepatic dysfunction and
increase of D-dimers3,4. It is also reported that these patients suffer from intense
pro-inflammation where hyper-cytokinemia predominates5,6.

The above characteristics lead to consider two main mechanisms of pathogenesis of this
critical condition: macrophage activation syndrome (MAS) and immune dysregulation. Early and
correct understanding of the mechanism and management are of prime importance. This can be
achieved only through a therapeutic protocol where the early recognition of the immune state
can be done with the use of biomarkers and with the delivery of the precise treatment aiming
to the correction of the immune dysregulation.

Data of the Hellenic Sepsis Study Group indicate that MAS can be diagnosed with reliability
using serum ferritin7. Concentrations greater than 4,420ng/ml possess diagnostic specificity
97.3% and negative predictive value 98%. According to these data, the risk of developing MAS
is greater among patients with comorbidities like type 2 diabetes mellitus and heart failure
who are prone to hyper-production of interleukin (IL)-1β by tissue macrophages8. A recent
retrospective analysis of patients with severe sepsis and MAS showed that the administration
of anakinra decreased 28-day mortality by 30%9. Anakinra is the recombinant antagonist of
human IL-1β receptor. IL-1β over-production is the hallmark of the pathogenesis of MAS.
Results of a phase III study in 906 patients showed that anakinra was a very safe drug: there
was neither excess mortality nor increased susceptibility to secondary infections9. Since
November 2017 the randomized clinical trial entitled "A trial of validation and restoration
of immune dysfunction in severe infections and sepsis, PROVIDE" (EudraCT number:
2017-002171-26, approval 78/17 by the National Ethics Committee, approval IS 75/17 by the
National Organization for Medicines, ClinicalTrials.gov NCT03332225). In this study patients
with sepsis and laboratory diagnosis of MAS are randomized to treatment with placebo or
anakinra for seven days. Enrolment was completed in December 2019 and no drug related adverse
events have been reported.

Recent unpublished data of the Hellenic Sepsis Study Group demonstrate that patients with
immune dysregulation have profound lymphopenia associated with elevated IL-6. This is in
accordance with evidence of the H1N1 pandemic where patients with pneumonia had substantial
lymphopenia and increased Τ regulatory lymphocytes (Treg). This increase of Τreg was
prominent among patients with comorbidities like diabetes mellitus, chronic heart failure and
chronic obstructive pulmonary disease10,11. The IL-6 blocker tocilizumab is a promising
candidate for the reversal of this immune dysregulation.

ESCAPE is an address to the personalized management of life-threatening organ dysfunction by
SARS-CoV-2. More precisely, patients infected by SARS-CoV-2 associated with MAS and immune
dysregulation will be administered treatment with anakinra and tocilizumab respectively.