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.
Drug: Anakinra alone (stages 2b/3)
Anakinra 300 mg 1/d Intravenous 5 days then dose tapering
Other Name: KINERET
Drug: Anakinra and Ruxolitinib (overcome stage 3)
Anakinra 300 mg od Intravenous (maximum14 days) Ruxolitinib 5 mg bid per os (maximum 28 days)
Other Name: KINERET and JAKAVI
Other: Standard of care
Routine clinical care for Covid-19
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.
AP-HM, Hôpital de la Conception
Marseille, Bouches-du-Rhône, France
Hôpital Sainte-Musse
Toulon, VAR, France
Sainte Anne Teaching Military Hospital
Toulon, Var, France
David DELARBRE, MD, Principal Investigator
French Army Health Service