The Current Use of Anti-IL6 and Corticosteroids in COVID-19 Patients with Cytokine-Release Syndrome

Marwa Amer; Mohammed Bawazeer; Talal Dahhan; Eiad Kseibi; Abid Butt; Mohammed Abujazar; Razan Alghunaim; Muath Rabee; Syed Moazzum Khurshid

doi:10.4103/sccj.sccj_38_20

REVIEW ARTICLE

Year : 2020 | Volume : 4 | 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

Correspondence Address:
Marwa Amer
Division of Pharmaceutical Care, College of Medicine, Alfaisal University, MBC #11, King Faisal Specialist Hospital and Research Center, PO Box: 3354, Riyadh 11211
Saudi Arabia

Source of Support: None, Conflict of Interest: None

Check

DOI: 10.4103/sccj.sccj_38_20

Abstract

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 3];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.^[1] COVID-19 patients with CRS can rapidly progress to acute respiratory distress syndrome (ARDS), shock, and multi-organ failure.^[2],[3],[4]

The initial symptoms commonly associated with mild grade CRS include fever, myalgia, tachycardia, and generalized weakness.^[5] 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.^[5]

Figure 1: Phases of COVID-19 disease progression, pathogenesis, and possible therapies.^[4],[5] 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

Click here to view

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.^[6] 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].^{[7],[8],[9],[10],[11],[12]} 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.^[13]

Table 1: Selected ongoing trials on anti-interleukin-6 drugs and steroids for COVID-19

Click here to view

Steroids have also been suggested as a CRS treatment for COVID-19 severe pneumonia.^[14] 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).^[15]

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.

Acknowledgments

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

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, et al. COVID-19: Consider cytokine storm syndromes and immunosuppression. Lancet 2020;395:1033-4.
2.	Alhazzani W, Al-Suwaidan FA, Al Aseri ZA, Al Mutair A, Alghamdi G, Rabaan AA, et al. The Saudi Critical Care Society Clinical Practice Guidelines on the management of COVID-19 patients in the intensive care unit. Saudi Crit Care J 2020;4:27-44. [Full text]
3.	Behera S, Jha SK, Singh NK, Khilnani GC, Mahajan A, Kumar S, et al. COVID-19: What we all intensivists should know. Saudi Crit Care J 2020;4:45-5. [Full text]
4.	Darden DB, Hawkins RB, Larson SD, Iovine NM, Prough DS, Efron PA. The clinical presentation and immunology of viral pneumonia and implications for management of coronavirus disease 2019. Crit Care Explor 2020;2:e0109.
5.	Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic staging proposal. J Heart Lung Transplant 2020;39:405-7.
6.	Cristina G, Stephen P. Cytokine release syndrome in the era of cancer immunotherapy. In: Current Concepts in Adult Critical Care. Ch. 20. Society of Critical Care Medicine; 2020.
7.	Xu X, Han M, Li T, Sun W, Wang D, Fu B, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A 2020;117:10970-5.
8.	Luo P, Liu Y, Qiu L, Liu X, Liu D, Li J. Tocilizumab treatment in COVID-19: A single center experience. J Med Virol 2020;92:814-8.
9.	Sciascia S, Aprà F, Baffa A, Baldovino S, Boaro D, Boero R, et al. Pilot prospective open, single-arm multicentre study on off-label use of tocilizumab in patients with severe COVID-19. Clin Exp Rheumatol 2020;38:529-32.
10.	Somers EC, Eschenauer GA, Troost JP, Golob JL, Gandhi TN, Wang L, et al. Tocilizumab for treatment of mechanically ventilated patients with COVID-19. Clin Infect Dis. 2020;ciaa954. doi:10.1093/cid/ciaa954.
11.	Hermine O, Mariette X, Tharaux PL, Resche-Rigon M, Porcher R, Ravaud P. CORIMUNO-19 Collaborative Group. Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. JAMA Intern Med. 2020:e206820. doi: 10.1001/jamainternmed.2020.6820.
12.	U. S. National Library of Medicine. NLMidentifier: NCT04320615. Available from: https://clinicaltrials.gov/ct2/show/study/NCT04320615. [Last acessed on 2020 Apr 02].
13.	Gritti G, Raimondi F, Ripamonti D, Riva I, Landi F, Alborghetti L, et al., Use of siltuximab in patients with COVID-19 pneumonia requiring ventilatory support. medRxiv 2020.04.01.20048561. doi: https://doi.org/10.1101/2020.04.01.20048561.
14.	Wang Y, Jiang W, He Q, Wang C, Wang B, Zhou P, et al., Early, low-dose and short-term application of corticosteroid treatment in patients with severe COVID-19 pneumonia: Single-center experience from Wuhan, China. medRxiv 2020.03.06.20032342. doi: https://doi.org/10.1101/2020.03.06.20032342
15.	RECOVERY Collaborative Group, Horby P, Lim WS, Emberson JR, Mafham M, Bell JL, et al. Dexamethasone in hospitalized patients with COVID-19-preliminary report. N Engl J Med. 2020:NEJMoa2021436. doi: 10.1056/NEJMoa2021436.