Supervisors info:
Γεώργιος Δημόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Ελένη Μάγειρα, Καθηγήτρια, Ιατρική Σχολή, ΕΚΠΑ
Αντώνιος Παπαδόπουλος, Καθηγητής, Ιατρική Σχολή, ΕΚΠΑ
Summary:
Since the first reported cluster of pneumonia cases in the Wuhan City, in China, SARS CoV-2 in less than four months rapidly spread globally accounting for million of deaths and creating havoc in the public health systems. The high rates of transmission, presence of asymptomatic carriers and international infrastructure connectivity, strikingly rendered COVID-19 a pandemic against which the governments were caught off guard, applying isolation measures as preventive strategies while the development of potent drugs and vaccines was under onward trial.
COVID-19 is a zoonotic disease, speculated to have originated from bats and pangolins. As a member of the Coronaviridae family SARS CoV-2 is an RNA virus which is comprized of three structural proteins, each playing a key role in the viral cycle of entry, replication and assembly. It is well recognized that the pathogenicity of severe COVID-19 lies in multiple levels. Numerous intertwined machineries of the innate and adaptive arms of the immune system are recruited aiming to mitigate the infection. Yet, the desired eradication of the virus occasionally comes at the cost of host's integrity, with multi-organ failure, ARDS, thrombotic events and death resulting from a rampant inflammatory cells activation, cytokine cascade, disrupted balance of the renin–angiotensin–aldosterone system signaling and ensuing tissue damage.
A cytokine whose role was recognized early in the course of the pandemic is IL-6, a pleiotropic interleukin synthesized by a variety of cells, most notably endothelial cells, fibroblasts and monocytes/macrophages during systemic inflammation, with serum concentrations promptly elevated to large quantities in critical disease. IL-6 is a major regulator of the acute-phase response and is implicated as a core element in the pathophysiology of the cytokine storm. Increased IL-6 levels were quickly associated in severe COVID-19 cases with respiratory failure, ARDS, multi-organ failure and poor survival, yielding a place for the application of a signaling inhibitor as an essential therapeutic approach.
Tocilizumab, an IL-6 receptor inhibitor upon which there is a 15years experience concerning connective tissue disorders and cytokine release syndrome, was initially tested with favorable outcomes in small cohorts with severe COVID-19 in Wuhan. Numerous studies that followed reported inconsistent findings regarding the benefit of tocilizumab administration in COVID-19 cases with variable degrees of respiratory failure. Nonetheless, the biggest population studies documented a benefit from the use of tocilizumab in severe COVID-19, in terms of survival, progression to invasive mechanical ventilation, ICU admission and hospital discharge.
The ESCAPE study was the first clinical trial designed to examine the potential of personalized immunotherapy in the clinical improvement of critical COVID-19. Based on previous findings, two distinct immunophenotypes were recognized; macrophage activation-like syndrome (MALS) defined by serum ferritin >4,420 ng/mL and complex immune dysregulation (CID) defined by serum ferritin ≤4,420 ng/mL and low HLA-DR expression on CD14-monocytes. It included a total of 102 patients with ARDS either allocated to treatment with anakinra when MALS criteria or CID criteria with increased aminotransferases were met or tocilizumab when CID criteria with normal aminotransferases were met. The primary composite outcome of ≥25% decrease in the Sequential Organ Failure Assessment (SOFA) score and/or 50% increase in the respiratory ratio by day 8 was met in 58.3% of anakinra-treated patients and in 33.3% of tocilizumab-treated patients, being statistically significant in favor of anakinra immunotherapy. No differences were found in the secondary outcomes of 28-day mortality and change of SOFA score by day 28 between the two groups. Survivors at day 28 who received anakinra were distributed to lower severity levels of the WHO clinical progression scale than patients who received tocilizumab (p=0.008) and the median time to hospital discharge was also less in the anakinra arm. Even though the overall results favored anakinra over tocilizumab, provided that the ESCAPE study was a non randomized, open-label trial of limited population, only limited assumptions can be made for the role of tocilizumab in complex immune dysregulation. There is a need for larger randomized, double-blind, double-dummy trials to further examine those results.
