|Year : 2020 | Volume
| Issue : 5 | Page : 21-24
The Current Use of Anti-IL6 and Corticosteroids in COVID-19 Patients with Cytokine-Release Syndrome
Marwa Amer1, Mohammed Bawazeer2, Talal Dahhan2, Eiad Kseibi2, Abid Butt2, Mohammed Abujazar2, Razan Alghunaim1, Muath Rabee2, Syed Moazzum Khurshid2
1 Division of Pharmaceutical Care, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
2 Department of Critical Care Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
|Date of Submission||30-Aug-2020|
|Date of Decision||01-Sep-2020|
|Date of Acceptance||25-Oct-2020|
|Date of Web Publication||7-Dec-2020|
Division of Pharmaceutical Care, College of Medicine, Alfaisal University, MBC #11, King Faisal Specialist Hospital and Research Center, PO Box: 3354, Riyadh 11211
Source of Support: None, Conflict of Interest: None
Cytokine-release syndrome (CRS) includes overproduction of inflammatory cytokines, termed a “cytokine storm,” which has been observed in a large proportion of critically ill COVID-19 patients. Patients diagnosed with CRS rapidly progress to cardiovascular collapse and multi-organ failure and carry a high mortality rate. Therefore, early detection, treatment, and prevention of cytokine storms are important. Immunomodulators, such as interleukin-6 (IL-6) antagonists, have recently emerged as an alternative therapeutic option for COVID-19 patients with cytokine storms. In preparation for a clinical trial, we searched the PUBMED, EMBASE, and COCHRANE databases to obtain related publications on the use of immunotherapies in CRS and CRS with COVID-19. We also included major review articles and recent guidelines. In our proposal, we aim to evaluate the efficacy and safety of anti-IL-6 alone versus anti-IL-6 and corticosteroid combination in COVID-19 critically ill patients with CRS. Our primary outcomes are duration of mechanical ventilation and 28-day ventilator-free days.
Keywords: COVID-19, critically ill patients, cytokine-release syndrome, cytokine storms
|How to cite this article:|
Amer M, Bawazeer M, Dahhan T, Kseibi E, Butt A, Abujazar M, Alghunaim R, Rabee M, Khurshid SM. The Current Use of Anti-IL6 and Corticosteroids in COVID-19 Patients with Cytokine-Release Syndrome. Saudi Crit Care J 2020;4, Suppl S1:21-4
|How to cite this URL:|
Amer M, Bawazeer M, Dahhan T, Kseibi E, Butt A, Abujazar M, Alghunaim R, Rabee M, Khurshid SM. The Current Use of Anti-IL6 and Corticosteroids in COVID-19 Patients with Cytokine-Release Syndrome. Saudi Crit Care J [serial online] 2020 [cited 2023 Feb 8];4, Suppl S1:21-4. Available from: https://www.sccj-sa.org/text.asp?2020/4/5/21/302578
| Introduction|| |
The ongoing COVID-19 pandemic has overwhelmed clinicians, in part because the course of the disease has been unpredictable and has triggered syndromes not usually associated with viral infections at current rates. One of these is cytokine-release syndrome (CRS) which defined as an exaggerated immune response mediated by B-cells, T-cells, macrophages, and natural killer cells. The activation of these inflammatory cells leads to their increased proliferation, amplified cytokine release (“cytokine storm”), secondary endothelial damage, cardiovascular collapse, and subsequent death. A previous study reported that the hyperinflammatory state in CRS resembles secondary hemophagocytic lymphohistiocytosis and is a contributing factor to COVID-19-associated mortality. COVID-19 patients with CRS can rapidly progress to acute respiratory distress syndrome (ARDS), shock, and multi-organ failure.,,
The initial symptoms commonly associated with mild grade CRS include fever, myalgia, tachycardia, and generalized weakness. Early intensive care unit (ICU) admission is recommended because the condition of these patients can deteriorate severely once CRS sets in. In patients with moderate-to-severe CRS, the available treatments include anti-interleukin (IL)-6 drugs (tocilizumab, sarilumab, and siltuximab) and corticosteroids. [Figure 1] illustrates the phases of COVID-19 disease progression, pathogenesis, and possible therapies.
|Figure 1: Phases of COVID-19 disease progression, pathogenesis, and possible therapies., During a respiratory infection, airway epithelial cells, natural killer cells, and CD8 T-cells release interferon gamma to limit viral replication. In addition, IL–6 and IL-8 are also released. High levels of IL-17, tumor necrosis factor-α, and IL-4 have also been observed. However, IL-6 appears to be the foundation for this inflammatory cascade and therefore plays an important role in the treatment of CRS. ARDS: Acute respiratory distress syndrome, CRP: C-reactive protein, LDH: Lactate dehydrogenase, JAK: Janus kinase, SIRS: Systemic inflammatory response syndrome, NT-proBNP: N-terminal pro B-type natriuretic peptide, GM-CSF: Granulocyte macrophage colony-stimulating factor|
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CRS is typically associated with chimeric antigen receptor T-cell therapy, and there is evidence in the literature on the effective use of anti-IL-6 immunotherapies for CRS. Tocilizumab is a monoclonal antibody against IL-6 receptor (IL-6R). It is typically dosed at 4–8 mg/kg intravenous (IV) once, and a second dose may be given in case of unsatisfactory response to the first dose. The efficacy of tocilizumab in treating severe or critical COVID-19 patients has been evaluated in several studies, which are summarized in [Table 1].,,,,, However, these studies are criticized by small sample size, preliminary data, absence of a control arm, and possible selection bias. Moreover, many papers are from preprint servers such as Medrxiv.org, which are preliminary reports that have not been peer reviewed. Another immunological therapy is the anti-IL-6 chimeric monoclonal antibody, siltuximab, utilized in patients with CRS with persistent elevation of IL-6 levels refractory to tocilizumab. Sarilumab (anti-IL-6R monoclonal antibody) is a new IV formulation available as part of a clinical trial. In an Italian case series, 21 COVID-19 patients, requiring continuous positive airway pressure ventilation or noninvasive ventilation, received siltuximab at a dose range of 700–1200 mg once through compassionate use. Of these 21 patients, seven improved, nine stabilized, and five deteriorated, including one case of death.
|Table 1: Selected ongoing trials on anti-interleukin-6 drugs and steroids for COVID-19|
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Steroids have also been suggested as a CRS treatment for COVID-19 severe pneumonia. The decision to use corticosteroids as an immunomodulator in early symptoms of a cytokine storm is reasonable and should be weighed with the possible side effects, and those have not been fully investigated with COVID-19 patients. The preliminary results from the ongoing RECOVERY trial suggest that dexamethasone use resulted in a lower 28-day mortality rate among patients requiring invasive mechanical ventilation as compared to the standard of care group (29.3% vs. 41.4%; relative risk [RR], 0.65; 95% confidence interval [CI]: 0.51–0.81) and those requiring supplemental oxygen therapy without mechanical ventilation (23.3% vs. 26.2%; RR, 0.80; 95% CI: 0.7–0.9).
As of August 18, 2020, none of the ongoing trials have addressed the question we are proposing in our study. Therefore, we will conduct a prospective, multicenter, multinational observational cross-sectional study to evaluate the efficacy and safety of anti-IL-6 alone versus anti-IL-6 plus corticosteroid combination in COVID-19 critically ill patients with CRS. Data will be collected from the Viral Infection and Respiratory Illness Universal Study registry; our institution is a part of this registry. This study is an ancillary study approved by the Society of Critical Care Medicine Scientific Review Committee. Our primary outcomes are duration of mechanical ventilation and 28-day ventilator-free days. This study is approved by the Research Ethics Committee and registered at ClinicalTrials. gov (Identifier: NCT04486521). At our institution, tocilizumab is administered for severe COVID-19 based on elevated inflammatory markers and rapidly worsening respiratory status. Steroid use was generally not commonly recommended prior to RECOVERY trial, and its use in patients with ARDS was at the decision of the critical care physicians. The STROBE checklist will be followed in conducting this study.
| Conclusion|| |
Based on the brief literature review presented here, it is clear that immunotherapy for COVID-19 patients has potential, particularly in those patients presenting with early signs of a cytokine storm with impending CRS. However, a complete clinical trial will be needed to fully elucidate the efficacy of immunotherapy for COVID-19 patients.
Our study will provide further insights into whether anti-IL-6 drugs alone provide the same efficacy and clinical outcomes with a reasonable side-effect profile compared with anti-IL-6 and steroid combination. In addition, our findings will help to clarify whether anti-IL-6 drugs can serve as steroid-sparing agents in COVID-19 patients with cytokine storms. Moreover, we will assess whether the risk of secondary infection would outweigh the benefits of using such combination in COVID-19 patients. Furthermore, the potential use of various doses and types of anti-IL-6 and steroids will be evaluated.
We thank the ICU physicians, ICU nurses, ICU respiratory therapists, ICU satellite pharmacists, and ICU clinical pharmacists of KFSH and RC for their efforts to save the lives of ICU patients and their bravery in fighting the COVID-19 pandemic. We also thank Maal Abualkhair and Abeer Alfirm for their help in data collection.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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