Anakinra shows therapeutic potential in critically ill COVID-19 patients

A team of international scientists recently conducted an open-level clinical trial to investigate the effects of personalized immunotherapy on critically ill coronavirus disease 2019 (COVID-19) patients. Their findings suggest that treatment with an interleukin-1 (IL-1) receptor antagonist, anakinra, can improve the clinical output of severe COVID-19 patients. The study is currently available on the medRxiv* preprint server.

Background   

Since the emergence of the COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), several studies have been done to understand patient-specific clinical presentations of the disease. It is now well-documented that critically ill COVID-19 patients are frequently associated with immune system dysregulation, which is characterized by increased proinflammatory cytokine level, proinflammatory/anti-inflammatory imbalance, reduced blood lymphocyte level, and increased blood ferritin level.

Blood ferritin level and expression of human leukocyte antigen (HLA)-DR on circulating monocytes are two well-studied biomarkers of immune dysregulation, which are clinically used to diagnose macrophage activation syndrome (MAS) and complex immune dysregulation (CID), respectively.  

According to the published literature, treatment of MAS patients with an IL-1 receptor antagonist, anakinra, has survival benefits. Similarly, treatment of circulating monocytes obtained from CID patients and COVID-19 patients with acute respiratory distress syndrome (ARDS) with an IL-6 antagonist, tocilizumab, can restore the expression of HLA-DR.

Study design

Based on these observations, the current study scientists conducted an open-level phase II clinical trial (ESCAPE trial) to investigate the treatment efficacy of anakinra and tocilizumab on critically ill COVID-19 patients presented with MAS or CID, respectively.

Specifically, they selected 4420 ng/ml of ferritin as a cutoff level to diagnose MAS in COVID-19 patients. Their analysis revealed that about 25% of COVID-19 patients with ARDS have MAS (ferritin level more than 4420 ng/ml) and the remaining 75% had CID (lower level of HLA-DR expression on circulating monocytes). Patients with a sequential organ failure assessment score of more than 2, or those diagnosed with ARDS, were regarded as having organ dysfunction.

The patients with MAS or CID were treated intravenously with anakinra or tocilizumab, respectively. However, CID patients with higher than normal aminotransferase levels were also treated with anakinra.

The primary outcome assessed in the trial was at least a 25% reduction in organ failure assessment score and/or at least 50% induction in respiratory ratio (PaO2/FiO2 ratio) by day 8. In addition, the mortality rate by day 28, change in organ failure assessment score by day 28, and change in serum biomarkers and peripheral blood mononuclear cell (PBMC)-mediated cytokine production were assessed as secondary outcomes.    

Important observations

Of the 102 enrolled patients, 60 were treated with anakinra and 42 were treated with tocilizumab. The baseline characteristics of all enrolled patients were the same.

About 58% of the anakinra-treated patients and 33% of the tocilizumab-treated patients met the primary outcome of the trial. However, there was no difference in the mortality rate and change in organ failure assessment score by day 28 between the two treatment groups. Regarding other biomarkers, an induction in lymphocyte count and the respiratory ratio was observed in anakinra-treated patients by day 8. Moreover, a reduction in blood ferritin level and an induction in HLA-DR expression on monocytes were observed by day 4 in anakinra-treated and tocilizumab-treated patients, respectively.

PBMCs obtained from anakinra-treated patients had shown increased capacity of IL-6 production by day 4, which in turn was associated with lower disease severity by day 28. However, patients treated with tocilizumab did not show such characteristics. Moreover, the duration of hospital stay was lower in anakinra-treated patients (20 days) compared to that in tocilizumab-treated patients (31 days). Patients treated with tocilizumab showed higher risk of developing a secondary infection than anakinra-treated patients.

Study significance

The ESCAPE trial aimed to investigate the effects of personalized immunotherapy on critically ill COVID-19 patients. The patients enrolled in this trial are categorized based on two immune dysfunctions, MAS and CID.

Overall, the findings revealed that anakinra treatment is more effective than tocilizumab treatment in reducing the organ failure assessment score and increasing the respiratory ratio of COVID-19 patients who are categorized by serum ferritin level and monocyte HLA-DR expression.  

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Journal reference:
Dr. Sanchari Sinha Dutta

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.

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