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Table of Contents
EDITORIAL
Year : 2020  |  Volume : 10  |  Issue : 4  |  Page : 159-162

What's new in critical illness and injury science? Intravenous immunoglobulin for COVID-19 with severe or critical illness


1 Department of Emergency Medicine, Nazareth Hospital, Philadelphia, PA, USA
2 Department of Internal Medicine, Nazareth Hospital, Philadelphia, PA, USA

Date of Submission12-Jul-2020
Date of Acceptance12-Jul-2020
Date of Web Publication29-Dec-2020

Correspondence Address:
Dr. Andrew C Miller
Department of Emergency Medicine, Nazareth Hospital, 2601 Holme Avenue, 3rd Floor, Marian Building, Philadelphia, PA 19152
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJCIIS.IJCIIS_192_20

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How to cite this article:
Miller AC, Venkatachalam S. What's new in critical illness and injury science? Intravenous immunoglobulin for COVID-19 with severe or critical illness. Int J Crit Illn Inj Sci 2020;10:159-62

How to cite this URL:
Miller AC, Venkatachalam S. What's new in critical illness and injury science? Intravenous immunoglobulin for COVID-19 with severe or critical illness. Int J Crit Illn Inj Sci [serial online] 2020 [cited 2021 Jan 21];10:159-62. Available from: https://www.ijciis.org/text.asp?2020/10/4/159/305297



Since emerging in December 2019, the coronavirus disease 2019 (COVID-19) pandemic caused by the beta-coronavirus severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) virus has resulted in over 66.5 million cases worldwide and over 1.53 million deaths (as of December 6, 2020). Roughly 20% of patients require hospitalization, with one-quarter of those necessitating intensive care unit (ICU) admission for reasons including refractory hypoxemia, shock, or multiple organ failure.[1],[2] The lack of therapies with data demonstrating efficacy resulted in many turning to less substantiated treatments supported by case reports or series, small nonrandomized studies, or even intellectual intuition. These have included (in part) antiviral therapies, immunomodulators, blood products, and traditional medications. This editorial focuses on one such therapy: intravenous immunoglobulin (IVIG) to treat severe or critical illness induced by COVID-19.

To date, seven human coronaviruses (CoV) have been identified.[2] Four of them are globally distributed and account for about 15% of common colds, whereas SARS-CoV, Middle-East Respiratory Syndrome CoV (MERS-CoV), and SARS-CoV-2 are zoonotic epidemic viruses that can cause severe respiratory infections and fatalities. CoV shares some morphological and functional properties that may be associated with cross-reactive immune responses, which may have important therapeutic implications.[3] A thorough discussion of the pathophysiology is outside the scope of this discussion, but interested readers may consider reviewing the included references.[3],[4] Cross-reactivity has been described among human CoVs of the same genus, particularly the beta-CoV, which include SARS-CoV, MERS-CoV, and SARS-CoV-2.[5],[6],[7]

IVIG preparations consist of highly purified immunoglobulins G (mostly IgG), obtained from 1000 to 15,000 healthy donors per batch.[8] It is frequently used for treating various autoimmune and inflammatory diseases. In general, the dose of IVIG for the therapeutic purposes is 2 g/kg infused for up to 5 consecutive days.[9] IVIG has been explored in over 100 diseases as an off-label drug. It exerts its therapeutic benefits by several mutually nonexclusive mechanisms targeting both soluble and cellular mediators of the inflammatory immune response.[9] The multitude of anti-inflammatory mechanisms, safety record, and preclinical data prompted clinical evaluation of IVIG in the management of severe and critically ill COVID-19 patients.[9]

In vitro studies supported the idea that, commercially, IVIG products contained antibodies with significant neutralization capacity against SARS-CoV-2 and SARS-CoV but not MERS.[3] After multiple case reports and series touted its efficacy, many began to use IVIG in the treatment of severe and critically ill COVID-19 patients, particularly for patients with central nervous system manifestations.[10],[11],[12],[13],[14],[15],[16],[17],[18] Of note, many of these cases had comorbid illnesses or chronically immunosuppressed states, for which IVIG may be an appropriate treatment,[10],[11],[18],[19] while others have touted high-dose IVIG pulse therapy as a means to prevent chronically immunosuppressed patients from contracting COVID-19.[20]

A listing of randomized and nonrandomized clinical studies in adult patients with severe or critical illness due to COVID-19 is presented in [Table 1], including two randomized[21],[22] and four nonrandomized clinical studies.[23],[24],[25],[26] Three studies were excluded from this review. The first, a randomized study, was excluded for quality concerns including high risk for reporting bias.[27] Data for all patients were only reported nonnumerically in graphical format, with numerical data reported for unplanned subgroup analyses. The second, a randomized study preprint, was excluded because it compared two experimental therapies (Anakinra/IVIG vs. Tocilizumab) without a control or usual care arm.[28] Finally, a nonrandomized study that compared early (<48 h) to late (≥48 h) IVIG treatment for COVID-19 was excluded because there was no non-IVIG treatment or usual care arm.[26] The risk of bias was assessed for each study using the ROBINS-I and GRADE tools.[29],[30]
Table 1: The characteristics of the included studies assessing intravenous immunoglobulin for management of coronavirus disease 2019

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The results of included studies are summarized in [Table 2]. Of note, when compared to usual care, IVIG treatment for COVID-19 has shown no benefit on hospital mortality (three studies, 973 patients, IVIG 196 (40.6%) versus usual care 186 (38.0%); evidence certainty High),[21],[22],[23],[24],[25] no benefit on 28-day mortality,[24],[25] and no benefit on 60-day mortality.[25] In addition, no benefit was observed for the need for invasive mechanical ventilation[22],[24] or ICU length-of-stay (LOS).[21],[22] Moreover, hospital LOS was longer with IVIG use (four studies, 1318 participants; evidence certainty Moderate).[21],[22],[24],[25] It should be noted that these data and conclusions should not be extrapolated to hyperimmune anti-COVID-19 IVIG. Investigations of this agent are currently planned or underway.[31],[32]
Table 2: Summary of the clinical effects of intravenous immunoglobulin in admitted patients with coronavirus disease 2019

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In conclusion, available evidence suggests that IVIG treatment for patients with severe or critical COVID-19 illness does not decrease hospital mortality and may prolong hospital LOS. Routine use of IVIG in severe or critically ill COVID-19 patients without other indications for its use is not advised.



 
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Díez JM, Romero C, Alert VJ, Perez BM, Rodon J, Honrubia JM, et al. Cross-neutralization activity against SARS-CoV-2 is present in currently available intravenous immunoglobulins. Immunotherapy 2020;12:1247-55.  Back to cited text no. 3
    
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Prete M, Favoino E, Catacchio G, Racanelli V, Perosa F. SARS-CoV-2 infection complicated by inflammatory syndrome. Could high-dose human immunoglobulin for intravenous use (IVIG) be beneficial? Autoimmun Rev 2020;19:102559. PMID: 32361195.  Back to cited text no. 8
    
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Shi H, Zhou C, He P, Huang S, Duan Y, Wang X, et al. Successful treatment with plasma exchange followed by intravenous immunoglobulin in a critically ill patient with COVID-19. Int J Antimicrob Agents 2020;56:105974. PMID: 33214093.  Back to cited text no. 14
    
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Muccioli L, Pensato U, Bernabè G, Ferri L, Tappatà M, Volpi L, et al. Intravenous immunoglobulin therapy in COVID-19-related encephalopathy. J Neurol 2020. Available from: http://link.springer.com/10.1007/s00415-020-10248-0. [Last accessed on 2020 Jun 12].  Back to cited text no. 15
    
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Lanza M, Polistina GE, Imitazione P, Annunziata A, Di Spirito V, Novella C, et al. Successful intravenous immunoglobulin treatment in severe COVID-19 pneumonia. IDCases 2020;21:e00794.  Back to cited text no. 16
    
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Cao W, Liu X, Bai T, Fan H, Hong K, Song H, et al. High-dose intravenous immunoglobulin as a therapeutic option for deteriorating patients with coronavirus disease 2019. Open Forum Infect Dis 2020;7:ofaa102.  Back to cited text no. 17
    
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Erdogan C, Ciftci B, Kizilaslan D, Ekinci M, İptec G, Gemici Aİ, et al. High-dose intravenous immunoglobulin therapy for novel coronavirus disease 2019: A brief report of two cases. Ain-Shams J Anesthesiol 2020;12:39.  Back to cited text no. 18
    
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Tatar E, Karatas M, Bozaci I, Ari A, Acar T, Simsek C, et al. Intravenous immunoglobulin and favipiravir treatment for a kidney transplant patient with severe Covid-19 pneumonia. Transfus Apher Sci 2020:102904. PMID: 32344202  Back to cited text no. 19
    
20.
Prada V, Benedetti L, Cocito D, Briani C, Orazio NE, Gallia F, et al. High-dose immunoglobulin pulse therapy and risk of Covid19 infection. J Neurol 2020. Available from: http://link.springer.com/10.1007/s00415-020-10146-5. [Last accessed on 2020 Jun 12].  Back to cited text no. 20
    
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Gharebaghi N, Nejadrahim R, Mousavi SJ, Sadat-Ebrahimi SR, Hajizadeh R. The use of intravenous immunoglobulin gamma for the treatment of severe coronavirus disease 2019: A randomized placebo-controlled double-blind clinical trial. BMC Infect Dis 2020;20:786.  Back to cited text no. 21
    
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Tabarsi P, Barati S, Jamaati H, Haseli S, Marjani M, Moniri A, et al. Evaluating the effects of intravenous immunoglobulin (IVIg) on the management of severe COVID-19 cases: A randomized controlled trial. Int Immunopharmacol 2020:107205. PMID: 32807652.  Back to cited text no. 22
    
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Esen F, Özcan PE, Orhun G, Polat Ö, Anaklı İ, Alay G, et al. Effects of adjunct treatment with intravenous Octagam on the course of severe COVID-19: Results from a retrospective cohort study. Curr Med Res Opin 2020. PMID: 33214093. Available from: https://www.tandfonline.com/doi/full/10.1080/03007995.2020.1856058. [Last accessed on 2020 Jun 12].  Back to cited text no. 23
    
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Liu J, Chen Y, Li R, Dong X, Li Y, Xu Q, et al. Intravenous immunoglobulin treatment for patients with severe COVID-19: A retrospective multi-center study. Research Square 2020. Available from: https://www.researchsquare.com/article/rs-52428/v1. [Last accessed on 2020 Jun 12].  Back to cited text no. 24
    
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Xie Y, Cao S, Dong H, Li Q, Chen E, Zhang W, et al. Effect of regular intravenous immunoglobulin therapy on prognosis of severe pneumonia in patients with COVID-19. J Infect 2020;81:318-56.  Back to cited text no. 26
    
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Sakoulas G, Geriak M, Kullar R, Greenwood K, Habib M, Vyas A, et al. Intravenous immunoglobulin (IVIG) significantly reduces respiratory morbidity in COVID-19 pneumonia: A prospective randomized trial. medRxiv 2020. Available from: https://www.medrxiv.org/content/10.1101/2020.07.20.20157891v1. [Last accessed on 2020 Jun 12].  Back to cited text no. 27
    
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Zanath M, Castillo ED, Gangemi AJ, Patel M, Chowdhury J, Verga S, et al. Anakinra and intravenous igg versus tocilizumab in the treatment of COVID-19 pneumonia. medRxiv 2020. Available from: https://www.medrxiv.org/content/10.1101/2020.09.11.20192401v1. [Last accessed on 2020 Jun 12].  Back to cited text no. 28
    
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Sterne JA, Hernán MA, Reeves BC, Savović J, Berkman ND, Viswanathan M, et al. ROBINS-I: A tool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016;355:i4919.  Back to cited text no. 29
    
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Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011;64:383-94.  Back to cited text no. 30
    
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Ali S, Luxmi S, Anjum F, Muhaymin SM, Uddin SM, Ali A, et al. Hyperimmune anti-COVID-19 IVIG (C-IVIG) therapy for passive immunization of severe and critically ill COVID-19 patients: A structured summary of a study protocol for a randomised controlled trial. Trials 2020;21:905.  Back to cited text no. 31
    
32.
Esen F, Özcan PE, Orhun G, Polat Ö, Anaklı İ, Alay G, et al. Effects of adjunct treatment with intravenous Octagam on the course of severe COVID-19: Results from a retrospective cohort study. Curr Med Res Opin 2020;1. Available from: https://www.tandfonline.com/doi/ full/10.1080/03007995.2020.1856058. [Last accessed on 2020 Jun 12]. PMID: 33236646.  Back to cited text no. 32
    



 
 
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