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

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.[12] 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.[34] 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.[567]

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.[101112131415161718] Of note, many of these cases had comorbid illnesses or chronically immunosuppressed states, for which IVIG may be an appropriate treatment,[10111819] 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[2122] and four nonrandomized clinical studies.[23242526] 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.[2930]

Table 1

The characteristics of the included studies assessing intravenous immunoglobulin for management of coronavirus disease 2019

Author (year)	Design, Country (n)	Population, severity	Intervention (n)	Comparison (n)	Primary endpoints	Secondary end pointsA
Esen (2020)	Retrospective, Turkey (93)	Confirmed COVID-19B, severe and critical illnessC	IVIG (Octagam) 5%, 30 g/day for 5 days (51)	Usual care (42)	28 days all-cause mortality
Gharebaghi (2020)	RCT, placebo controlled, Iran (59)	Confirmed COVID-19B, severe and critical illnessC	IVIG (flebogamma) 5% DIF, 4 vials of 5 g IVIG daily for 3 consecutive days plus usual care (30)	Usual care plus placebo (29)	Hospital mortality	Hospital LOS
Liu (2020)D	Retrospective, multicenter, propensity score matching, China (850)	Confirmed COVID-19B, severe and critical illnessC	Stratified by IVIG regimen: high dose (≥10 g/day), low dose (<10 g/day), long course (≥8 days), short course (<8 days), early (≤48 h), and late (>48 h) after hospitalization (421)	Usual care (429)	28 days all-cause mortality	Hospital mortality, ICU LOS, hospital LOS
Shao (2020)D	Multicenter, retrospective China (325)	Confirmed COVID-19B, severe and critical illnessC	IVIG, not standardized dose (174)	Usual care (151)	Hospital mortality at 28 and 60 days	Hospital LOS, disease duration
Tabarsi (2020)	RCT, Iran (84)	Confirmed COVID-19B, severe and critical illnessE	IVIG 400 mg/kg IV for 3 days with premedication including hydrocortisone 100 mg IV (52)	Usual care (32)	Need for invasive mechanical ventilation	ICU LOS, hospital LOS

A Only those secondary end-points relative to this discussion are included,

B Diagnosis made by real-time RT-PCR,

C According to the US National Institutes of Health classification,

D Preprint,

E As defined by the World Health Organization. IV: Intravenous, RCT: Randomized controlled trial, IVIG: IV immunoglobulin, ICU: Intensive care unit, LOS: length-of-stay, MV: Mechanical ventilation, COVID-19: Coronavirus disease 2019, RT-PCR: Reverse transcription-polymerase chain reaction

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),[2122232425] no benefit on 28-day mortality,[2425] and no benefit on 60-day mortality.[25] In addition, no benefit was observed for the need for invasive mechanical ventilation[2224] or ICU length-of-stay (LOS).[2122] Moreover, hospital LOS was longer with IVIG use (four studies, 1318 participants; evidence certainty Moderate).[21222425] 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.[3132]

Table 2

Summary of the clinical effects of intravenous immunoglobulin in admitted patients with coronavirus disease 2019

Variables	Studies, author (year)
	Esen (2020)	Gharebaghi (2020)	Liu (2020)A	Shao (2020)	Tabarsi (2020)
Hospital mortality, yes, n (%)		IVIG 6 (20%) versus non-IVIG 14 (48.3%); P=0.025	IVIG 166 (39%) versus non-IVIG 158 (36%); P=0.609		IVIG 24 (46%) versus non-IVIG 14 (43.8%); P=0.83
ICU mortality, yes, n (%)	IVIG 20 (39%) versus non-IVIG 26 (62%)**Controlling for baseline APACHE II, survival improved with IVIG (OR 2.2, 95% CI 0.9-5.4, P=0.091)**
28 days hospital mortality, yes, n (%)			IVIG 164 (39%) versus non-IVIG 154 (36%); P=0.357**Subgroup analysis: high dose (≥10 g/day) associated with decreased mortality (OR 0.33, 95% CI: 0.14-0.77; P=0.011)**	IVIG 22 (13%) versus non-IVIG 20 (13%); P=0.872
60 days hospital mortality, yes, n (%)				IVIG 33 (19%) versus non-IVIG 21 (14%); P=0.222
Hospital LOS, days, median (IQR 25-75)		IVIG 9 (7-13) versus Control 7 (6-9); P=0.014	IVIG 15 (10-22) versus non-IVIG 14 (8-19); P=0.005	IVIG 23.5 (16.0-33.0) versus non-IVIG 16.0 (13.0-22.0); P<0.001	IVIG 8.5 (6-12) versus non-IVIG 5.5 (4-8); P=0.003
ICU LOS, days, median (IQR 25-75)		IVIG 4 (3-6) versus Control 3 (2-4); P=0.101	Listed as a measured outcome but not reported		IVIG 5 (3-7) versus non-IVIG 4 (2-7); P=0.72
Invasive mechanical ventilation, n (%)			IVIG 16 (3.8%) versus non-IVIG 16 (3.8%); P=0.973		IVIG 21 (40%) versus non-IVIG 10 (31%); P=0.39

A Preprint. IV: Intravenous, IVIG: IV immunoglobulin, IQR 25-75: Interquartile range 25th percentile-75th percentile, OR: Odds ratio, LOS: Length-of-stay, ICU: Intensive care unit, CI: Confidence interval

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.