Can emapalumab be life saving for refractory, recurrent, and progressive cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and Janus kinase inhibitors

Abstract

Although many potent drugs have been used for cytokine storm, mortality is high for patients with coronavirus disease-2019 (COVID-19), which is followed up in the intensive care unit. Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. However, IFN-γ plays a key role in both primary and secondary cytokine storms. If the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Anakinra, an interleukin-1 (IL-1) antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19. However, sometimes, despite these treatments, the patient's clinical course does not improve. Emapalumab (Eb) is the human immunoglobulin G1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.

Introduction

The coronavirus disease-2019 (COVID-19) caused by the SARS-CoV-2 virus is mild in most patients and resolves without sequelae. The infection can be severe and fatal in patients with chronic disease and immunodeficiency. Although many potent drugs have been used for cytokine storm, mortality is high for patients with COVID-19, which is followed up in the intensive care unit (ICU). We think that emapalumab (Eb) can be effective in a refractory, persistent, and progressive cytokine storm. A clinical trial study on the effectiveness of Eb in COVID-19 was started on 27 March 2020 in Italy.[1]

Discussion

Interferons (IFNs) are the major cytokines of the antiviral defense system released from many cell types. IFNs have three types as Type I (IFN-α and IFN-β), Type II (IFN-γ), and Type III (IFN-λ). Once released, Type I IFNs bind to specific receptors on the target cells, leading to the expression of proteins that will prevent the viruses from producing and proliferate RNA or DNA. IFN-γ can be used in the treatment of COVID-19 to increase human host defense.[2,3] The release of IFN Type I and Type III from T-lymphocytes can be protective against COVID-19 and reduce the viral load.[3] At first, low IFN-α and IFN-β levels lead to increased viral infection.[3] However, when the viral infection advance, increased IFN-α and IFN-β levels become dangerous.[2,3] In this situation, IFN blockers can be used. IFN may have a dual effect on COVID-19 infection, and human host factors such as genetic and comorbidity will play a major role in these effects.[4]

IFN-γ can be helpful in COVID-19 treatment by increasing the human host response against SARS-CoV-2; however, it has been determined that IFN Type I and Type II cause angiotensin-converting enzyme 2 (ACE2) upregulation. ACE2 upregulation can increase the viral load.[4] INF-γ release can be life threatening for critically ill ICU patients with COVID-19. INF-γ blocking may be the basis of the treatment in the patients.[4] IFN-γ has been reported to be responsible for cytokine storm in SARS-COV infection.[5] The INF-γ level is top in critically ill ICU patients with COVID-19.[6,7,8] The release of many cytokines increases during the cytokine storm caused by COVID-19. These increased cytokines are IFN-γ, tumor necrosis factor-α, interleukin-2 (IL-2), and IL-7.[7,9] Besides, the levels of granulocyte colony-stimulating factor, a glycoprotein, and the level of chemokine such as inducible protein 10 and monocyte chemoattractant protein 1 are increased during cytokine storm.[7,9] Anakinra, an IL-1 antagonist, tocilizumab, an IL-6 antagonist, and Janus kinase (JAK) inhibitors are successfully used in cytokine storm caused by COVID-19.[9] Signal transducers and activators of transcription (STATs) are necessary for the transcription of some target genes of IL-6 and IFN-γ cytokines. Some STATs are stimulated by both Type I and Type II IFNs. JAK inhibitors successful in the treatment of COVID-19 infection suggest that IFN-γ may play an important role in the virus-induced cytokine storm.[10] Although IFN-γ plays a protective role against COVID-19 infection at optimum levels, it may be responsible for cytokine storm in critically ill ICU patients with COVID-19.

There may be many primary or secondary causes of the cytokine storm. Increased CD8+ T-cells, IFN-γ, and IL-33 play a role in primary hemophagocytic lymphohistiocytosis (HLH) etiology.[11] Secondary HLH is for an exaggerated immune system response during viral infection, malignancy, or rheumatological diseases.[10] IFN-γ plays a key role in both primary and secondary cytokine storms.[11] In cytokine storm, the level of many cytokines increases, including IFN-γ, IL-2, IL-6, IL-10, and IL-18 in hyperactivation of T-lymphocytes and defective NK-cell function.[10] Specific antigens induce IFN-γ production by stimulating natural killer T-cells, CD4+ helper T-cells, and CD8+ cytotoxic T-cells.[12] Excessive IFN-γ production and activity lead to tissue damage and multiple organ failure.[12]

Eb is the human IgG1 monoclonal antibody and is a potent and noncompetitive antagonist of IFN-γ. Eb has been used in individuals of all ages to treat refractory, recurrent, and progressive primary HLH since 2018.[10,13] Eb also is thought to be effective in resistant secondary HLH, and its phase II-III study in adults continues.[12,14] Eb binds both free IFN-γ and IFN-γ-receptor (IFN-γ-R)-1 bound IFN-γ and disrupts the interaction of IFN-γ with IFN-γ-R1 and IFN-γ-R2 on the cell surface.[12] Eb inhibits the release of many pro-inflammatory cytokines.[12] Eb was found to be very effective in resistant, refractory, and progressive primary HLH. Besides, a patient was fully recovered after 14 days of Eb treatment in Epstein-Barr virus-related life-threatening HLH.[15] Eb has been shown to prevent graft rejection after allogeneic-hematopoietic stem cell transplantation.[16,17]

Treatment with a single agent may not be successful mostly in cytokine storm since many types of cytokines act a role in the etiology of the cytokine storm[10] IFN-γ acts a vital role in the etiology of many HLH. Eb can prevent recurrent, treatment-resistant, and progressive cytokine storm by fully blocking IFN-γ. The initial dose of Eb is 1 mg/kg twice a day, after continuing treatment with this dose for 1 week. The dose of it can be raised up to 10 mg/kg.[10] It is recommended to use EB in combination with dexamethasone.[10] When Eb is used in high doses and for a long time, it can cause severe side effects such as secondary infection, hypertension, and pyrexia.[10] However, the side effects are not seen as frequently with routine Eb doses.

Conclusion

IFN-γ blocker or IL blockers or JAK inhibitors may exacerbate the prognosis of severe patients with COVID-19 by causing a secondary infection.[18] However, if the cytokine storm is not treated urgently, it will be fatal; therefore, it should be treated immediately. Eb can be life saving for cytokine storm caused by COVID-19, which is resistant to anakinra, tocilizumab, and JAK inhibitors.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.