COVID-19 associated mortality remains high despite the advances in therapeutics such asdexamethasone. The severity of COVID-19 results from direct viral cytotoxicity, and theinflammatory response, which is associated with a hypercoagulable state, contribute tolethal hypoxemic pneumonia. During the SARS-CoV-2 replication phase, infected cellssecrete chemokines and die by activating the immune system locally. A local inflammatoryloop induces tissue destruction, which activates the immune system's circulating cells,leading to another amplifying loop called the cytokine storm. In these phenomena, theintegrity of the interferon pathway plays a significant role.Specific impairment of the interferon pathway has been identified in a subset of patientsand is associated with high Covid-19 severity. This subset of patients presentspreexisting autoimmune disease mediated by autoantibodies directed against IFN. Itrepresents 10.2% (101/987) of patients admitted in ICU with COVID-19 pneumonia, and theobserved mortality in this subgroup is 40%.The investigators hypothesized that plasma exchanges (PE) would eliminate theseautoantibodies while acting on other mechanisms of the pathogenesis of severe COVID-19,such as cytokine storm or hypercoagulability(7).The EPIC trial aims to demonstrate the efficacy of plasma exchange in the subpopulationof patients with anti-interferon autoantibodies and severe COVID-19 hospitalized inintensive care and on oxygen therapy, high flow or not, receiving non-ventilation orinvasive ventilation, on D28 survival.
As of 11/09/2020, 50,000,000 people have been infected with COVID-19 worldwide, and
1,200,000 people have died, mainly from acute respiratory distress syndrome (ARDS ). Only
Dexamethasone has shown survival improvement in patients hospitalized with severe
COVID-19 receiving oxygen or more invasive symptomatic treatment. Despite this
therapeutic advance, invasive ventilation is necessary in 30% of hospitalized cases, and
mortality remains high among ventilated patients (30-40%). This study suggests that it is
necessary to continue searching for a treatment to reduce this mortality rate further
while confirming that immunity modulation is a promising strategy.
The severity of COVID-19 results from direct viral cytotoxicity, the accompanying
inflammatory response associated with a state of hypercoagulability which contributes to
lethal hypoxemic pneumonitis. During the SARS-CoV-2 replication phase, infected cells
secrete chemokines and die by activating the immune system locally. A local inflammatory
loop induces tissue destruction, which activates the immune system's circulating cells,
leading to another amplifying loop called the cytokine storm. A high concentration of
pro-inflammatory interleukins characterizes this cytokine storm. It induces an
endothelial dysfunction that causes activation of the coagulation system and an increase
in vascular permeability. These mechanisms lead to COVID-19 pneumopathy, and the
pathologic examination reveals diffuse alveolar damage associated with a significant
inflammatory infiltrate and microthrombi. These lesions cause pulmonary dysfunction and
refractory hypoxia, which is the cause of mortality from COVID-19.
In these phenomena, the integrity of the type 1 interferon pathway seems to play a major
role and more particularly in COVID-19. Patients in whom the type I or III interferon
pathway is dysfunctional are particularly susceptible to viral damage. It is now known
that dysfunction of one of the interferon pathways exposes the host to a severe viral
infection such as fulminant viral hepatitis or severe influenza pneumonia caused. In a
study published in September in Science, Professor Jean-Laurent Casanova's team found in
10.2% (101/987) of patients with COVID-19 pneumonia neutralizing autoantibodies directed
against IFN-ω (13 patients), one of 13 types of IFN-α (36), or both (52); In this study,
the authors show that these autoantibodies neutralized the ability of IFN type I to block
SARS-CoV-2 infection. When a patient presents one of these autoantibodies, he is exposed
to an increased mortality risk compared to the healthy population. It is estimated at 40%
in the affected population versus less than 10% in the rest.
Plasma exchanges (PE) are a blood purification technique that eliminates auto-antibodies
in the context of autoantibodies driven pathologies, particularly in intensive care such
as autoimmune myasthenia gravis or Guillain Barré syndrome. This technique makes it
possible to purify the plasma containing immunoglobulins, cytokines, chemokines,
coagulation factors and replace it with plasma from healthy subjects or purified human
albumin. The theoretical ability to remove some of the pro-inflammatory substances,
toxins, and cellular components from the sick individual quickly identified plasma
exchange as a potential therapy for COVID-19. The discovery of anti-interferon
autoantibodies as a significant gravity factor leads us to hypothesize that PE would be
even more beneficial in this subpopulation.
To date, eight randomized clinical trials are in progress evaluating the interest of
plasma exchanges in COVID-19 on clinicaltrials.gov. The inclusion criteria in these
studies are broad. As plasma exchanges are an expensive therapy with limited
availability, it makes their use in all patients with severe COVID-19 impossible. In this
study, the investigators propose to demonstrate the efficacy of PE in the subpopulation
of patients with anti-interferon autoantibodies and severe COVID-19 hospitalized in
intensive care and on oxygen therapy, high flow or not, receiving invasive or
non-invasive ventilation on survival to D28.
Drug: Therapeutic plasma exchange
Plasma exchange techniques reported in COVID-19 vary from study to study. No consensus
exists on the use of a specific technique.
The use of a central venous catheter will be left to the discretion of investigators. If
so, central venous catheter will be inserted through the internal jugular or femoral
route under ultrasound control by a trained operator. After radiographic control of the
position of the catheter and the absence of complications in the placement of the
catheter, plasma exchanges will be carried out.
Three plasma exchanges of 1.5 plasma volume will be carried out every 48 hours on D1, D3
and D5. Plasma volume will be assessed by this equation VP = (1-Hct)x70xweight
Body(measured). The substitution volume will be 5% albumin as first intervention. The use
of a hemofiltration or centrifugation technique will be left to the discretion of each
center.
Other Name: Therapeutic plasma exchanges
Inclusion Criteria:
1. SARS-CoV-2 infection proven by PCR.
2. Positive detection of anti-interferon antibodies.
3. Patient, family or deferred consent (emergency clause).
4. Affiliation to a social security scheme (or exemption from affiliation). Inclusions
are possible also for protected patient (under guardianship and tutornship).
Exclusion Criteria:
1. Pregnant women, parturients and nursing mothers
2. Minor patient
3. Participation in another interventional trial in progress, with the objective, even
secondary, of reducing mortality
4. Indication to EPT for another associated pathology
5. Contra-indication to EPT, known allergy to albumin 5%.
6. Persons under court protection,
7. Disturbance of the haemostasis balance (PT<50%, APTT>1.5 and fibrinogen <1g/L)
8. Patient presenting a hemorrhagic diathesis (intracranial or digestive bleeding or
threatening the functional prognosis)
9. Any progressive and advanced pathology whose life expectancy is less than one month
10. Bacterial or viral infectious disease (HIV) explaining most of the aggravation
GHU Paris Psychiatrie et Neurosciences
Paris, France
Investigator: Aurélien Mazeraud, MD PHD
Investigator: Aurélien Mazeraud
Aurélien Mazeraud, MD, PhD
+33145657413
a.mazeraud@ghu-paris.fr