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In This Article
 »  Abstract
 » Introduction
 » Discussion
 » Conclusion
 »  References

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 Table of Contents    
SHORT COMMUNICATION
Year : 2021  |  Volume : 53  |  Issue : 3  |  Page : 226-228
 

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


1 Department of Internal Medicine, Ota and Jinemed Hospital, Istanbul, Turkey
2 Department of Rheumatology, Meram Tip Faculty, Necmettin Erbakan University, Konya, Turkey
3 Department of Biochemistry, Private Kucukcekmece Hospital, Istanbul, Turkey

Date of Submission21-Jul-2020
Date of Decision31-Dec-2020
Date of Acceptance17-May-2021
Date of Web Publication22-Jun-2021

Correspondence Address:
Dr. Erkan Cure
Department of Internal Medicine, Ota and Jinemed Hospital, Muradiye Mahallesi Nuzhetiye Cad, Deryadil Sokagi No: 1, Istanbul 34357
Turkey
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijp.IJP_615_20

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 » 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.


Keywords: COVID-19, cytokine storm, emapalumab, interferon, SARS-CoV-2


How to cite this article:
Cure E, Kucuk A, Cure MC. 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. Indian J Pharmacol 2021;53:226-8

How to cite this URL:
Cure E, Kucuk A, Cure MC. 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. Indian J Pharmacol [serial online] 2021 [cited 2021 Oct 22];53:226-8. Available from: https://www.ijp-online.com/text.asp?2021/53/3/226/318975





 » Introduction Top


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 Top


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 Top


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.



 
 » References Top

1.
Available from: https://www.clinicaltrials.gov/ct2/show/NCT04324021. [Last asscessed on 2020 Dec 14].  Back to cited text no. 1
    
2.
Nile SH, Nile A, Qiu J, Li L, Jia X, Kai G. COVID-19: Pathogenesis, cytokine storm and therapeutic potential of interferons. Cytokine Growth Factor Rev 2020;53:66-70.  Back to cited text no. 2
    
3.
Ye Q, Wang B, Mao J. The pathogenesis and treatment of the 'Cytokine Storm' in COVID-19. J Infect 2020;80:607-13.  Back to cited text no. 3
    
4.
Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, et al. SARS-CoV-2 Receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues. Cell 2020;181:1016-35.e19.  Back to cited text no. 4
    
5.
Huang KJ, Su IJ, Theron M, Wu YC, Lai SK, Liu CC, et al. An interferon-gamma-related cytokine storm in SARS patients. J Med Virol 2005;75:185-94.  Back to cited text no. 5
    
6.
Zhao M. Cytokine storm and immunomodulatory therapy in COVID-19: Role of chloroquine and anti-IL-6 monoclonal antibodies. Int J Antimicrob Agents 2020;55:105982.  Back to cited text no. 6
    
7.
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020;395:497-506.  Back to cited text no. 7
    
8.
Rahmati M, Moosavi MA. Cytokine-targeted therapy in severely ill COVID-19 patients: Options and cautions. EJMO 2020;4:179–80.  Back to cited text no. 8
    
9.
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.  Back to cited text no. 9
    
10.
Vallurupalli M, Berliner N. Emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis. Blood 2019;134:1783-6.  Back to cited text no. 10
    
11.
Behrens EM, Koretzky GA. Review: Cytokine storm syndrome: Looking toward the precision medicine era. Arthritis Rheumatol 2017;69:1135-43.  Back to cited text no. 11
    
12.
Al-Salama ZT. Emapalumab: First global approval. Drugs 2019;79:99-103.  Back to cited text no. 12
    
13.
Kaplon H, Reichert JM. Antibodies to watch in 2019. MAbs 2019;11:219-38.  Back to cited text no. 13
    
14.
Locatelli F, Jordan MB, Allen C, Cesaro S, Rizzari C, Rao A, et al. Emapalumab in children with primary hemophagocytic lymphohistiocytosis. N Engl J Med 2020;382:1811-22.  Back to cited text no. 14
    
15.
Lounder DT, Bin Q, de Min C, Jordan MB. Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections. Blood Adv 2019;3:47-50.  Back to cited text no. 15
    
16.
Merli P, Caruana I, De Vito R, Strocchio L, Weber G, Bufalo FD, et al. Role of interferon-γ in immune-mediated graft failure after allogeneic hematopoietic stem cell transplantation. Haematologica 2019;104:2314-23.  Back to cited text no. 16
    
17.
Lam MT, Coppola S, Krumbach OHF, Prencipe G, Insalaco A, Cifaldi C, et al. A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function. J Exp Med 2019;216:2778-99.  Back to cited text no. 17
    
18.
Ritchie AI, Singanayagam A. Immunosuppression for hyperinflammation in COVID-19: A double-edged sword? Lancet 2020;395:1111.  Back to cited text no. 18
    




 

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