Efficacy of Intravenous Anakinra and Ruxolitinib During COVID-19 Inflammation

During SARS-Cov2 infection with serious respiratory implication and high systemic inflammation level, intravenous ANAKINRA alone or associated with RUXOLITINIB for severe cases might reduce inappropriate systemic inflammatory response, improve breathing and decrease occurrence or duration of ARDS and associated mortality.

Two physiopathological phases exist during COVID-19 disease: The early phase is mainly induced by the virus itself. It is imperative not to decrease the immune host response during this phase by prohibiting the use of non steroidal anti-inflammatory drugs or corticosteroids at this stage and developing an anti-viral strategy. The late phase, around Day 7-9, depends only upon host response and is linked to an excessive inflammatory response with a major increase of inflammatory cytokines such as IL-6, MCP-1, GCSF indicative of IL-1b excess, as well as IP-10, MIP-1, indicative of IFNg signature, corresponding to a "cytokine storm". Clinical and biological features during Still's disease (complicated in 10% of cases with hemophagocytosic lymphohistiocytosis inducing cytopenia, hepatic insufficiency, major hyperferritinemia and multi-organ failure) are close to those reported during COVID-19 and underline physiopathological similarities.

Anakinra (KINERET) is an IL-1 pathway (IL-1ra) specific inhibitor that has been used for 15 years, also largely blocking IL-18 production. Adult Still's disease is very effectively treated with anakinra. During sepsis with hyperferritinemia, IL-1ra demonstrated patient survival improvement. Ruxolitinib (JAKAVI) inhibits the downstream IFNg pathway targeting JAK kinase receptor. It has recently proved its efficiency in hemophagocytosic lymphohistiocytosis refractory forms associated with a multi-organ failure.

Eligibility Criteria:
Inclusion Criteria:

* Confirmed respiratory tract SARS-coV-2 infection by at least one PCR on nasopharygeal sample or a bronchoalveolar lavage
* Patient hospitalized with clinical, biological and radiological features corresponding to the following stages :

  * Stage 2b: hypoxic pneumonia (respiratory frequency \> 30/mn, Sa02 \< 90 mmHg on room air) associated with a clear biological inflammatory syndrome (CRP \> 150 mg/l)
  * Stage 3: ARDS defined by a patient under mechanical ventilation with a ratio PaO2/FiO2 \< 300 for more than 24h
  * Evolved stage 3: ARDS according to previous definition associated with another organ failure or syndrome among:
* A state of shock with noradrenaline dosing \> 3mg/h
* Acute kidney failure oligo-anuric or justifying extra-renal purification
* Hepatocellular insufficiency or coagulopathy with a V factor \< 50%
* Myocarditis responsible for acute heart failure and or cardiogenic shock
* Hemophagocytic syndrome
* Hyperferritinemia \> 5000 ng/mL
* Subject or legal representative having expressed written consent after information
* Subject affiliated to or entitled to a social security regimen
* Patient presenting in a life-threatening emergency situation that does not allow consent to be obtained

Exclusion Criteria:

* Pregnancy or lactation
* Absolute neutrophil count less than 1.5 x 109/L
* Hepatic transaminases AST or ALT greater than 5 times normal values
* Platelet count less than 50,000 per mm3
* Solid organ or hematopoietic stem cell transplant patients
* Patients treated with immunosuppressants or immunomodulators
* Use of oral corticosteroids chronically at doses greater than 10 mg prednisone equivalent per day for a non-COVID-19 related condition.
* Uncontrolled autoimmune disease
* Patients with active, suspected or known, uncontrolled systemic bacterial, viral (excluding COVID-19) or fungal infections
* Hypersensitivity to anakinra and/or ruxolitinib and their excipients
* Vaccinations with live attenuated vaccines in the month prior to inclusion
* Patients with severe pre-existing uncontrolled organ dysfunction (heart, liver or kidney failure)
* Persons deprived of liberty by judicial or administrative decision or major persons under a legal protection measure.
* Person in exclusion period of another research protocol for SARS-CoV-2 infection.
* Person not mastering enough French understanding and reading to be able to consent to participate in the study.
* Persons under psychiatric care pursuant to Articles A3112-1 and L3113-1 who are not covered by the provisions of Article L1121-8
* Every condition which, according to investigator, might increase and compromise the person security in case of study participation or might interfere with research results.