International Journal of Critical Illness and Injury Science

: 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

Andrew C Miller1, Shobi Venkatachalam2,  
1 Department of Emergency Medicine, Nazareth Hospital, Philadelphia, PA, USA
2 Department of Internal Medicine, Nazareth Hospital, Philadelphia, PA, USA

Correspondence Address:
Dr. Andrew C Miller
Department of Emergency Medicine, Nazareth Hospital, 2601 Holme Avenue, 3rd Floor, Marian Building, Philadelphia, PA 19152

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;10:159-162

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 19 ];10:159-162
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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 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}

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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