Against the Storm: High-Dose IVIG as an Immunoregulatory Treatment Strategy for Severe COVID-19

Mass vaccination, mask-wearing and social distancing have helped to sharply reduce new U.S. COVID-19 cases from its peak of nearly 250,000 per day in early January. Still, as of early May — 15 months since the beginning of this pandemic — an average of 50,000 new COVID-19 cases were being reported on an average daily basis, with more than 5,000 new hospitalizations per day.¹ And while use of supplemental oxygen, dexamethasone and measures ranging from prone positioning to extracorporeal membrane oxygenation have helped to reduce case mortality, between 10 percent and 15 percent of hospitalized COVID-19 patients continue to succumb to acute respiratory distress syndrome (ARDS), sepsis, multiorgan failure and other disease complications.  

We now know that SARS-CoV-2 neutralizing monoclonal antibody preparations and as little as a single unit of high-titer COVID-19 convalescent plasma² are effective in reducing the likelihood of severe disease and hospitalization when administered to mildly ill at-risk COVID-19 patients within a few days following first symptoms. Yet in most hospitalized patients, neither these antibody-based treatments nor antiviral drugs such as remdesivir and lopinavir have been shown to reduce mortality or the need for ICU admission or mechanical ventilation.³ 

Numerous clinical and laboratory studies of the immunopathology of severe viral respiratory tract diseases provide the answer to this seeming paradox. Nonsevere respiratory viral infections generally induce physiologic release of inflammatory cytokines and chemokines by endothelial cells, mononuclear macrophages, dendritic cells and natural killer cells, which helps recruit leukocytes and plasma proteins to the infection site to help combat it.⁴ But excessive production of proinflammatory cytokines is commonly triggered in patients with severe acute viral pneumonias — most notably severe influenza and the SARS and MERS coronaviruses — resulting in a runaway hyperinflammatory process. Untreated, this “cytokine release syndrome” or “cytokine storm” can rapidly lead to a constellation of severe sequelae, including ARDS, multiorgan failure, disseminated intravascular coagulation, vasodilatory shock and death.^5,6 

The Unique Challenge of Cytokine Storm

Cytokine storm in COVID-19 patients is characterized by a sudden acute increase in circulating levels of numerous proinflammatory cytokines, growth factors and chemokines, notably including IL-6, IL-1, GM-CSF, TNF and IFN-y. Also elevated are nonspecific markers of inflammation such as C-reactive protein (CRP), whose levels have been found to correlate with severity. COVID-19 patients with cytokine storm typically have pneumonia that can quickly progress to ARDS and multiorgan failure. It is now apparent that the rapid clinical deterioration seen in hospitalized patients with SARS-CoV-2 infection is most often the result of injury caused by the exaggerated proinflammatory immune dysregulation, not direct viral damage.⁷  

Elevated IL-6 levels, the most frequently reported indicator of cytokine storm in hospitalized COVID-19 patients, have been strongly associated with shorter survival.⁸ Accordingly, numerous studies have investigated tocilizumab,* a licensed recombinant anti-IL-6 receptor monoclonal antibody, as a potential treatment. Conflicting results have been reported thus far, with some studies documenting meaningful survival or other clinical benefits with use of tocilizumab,^9,10,11,12 while others show no benefit at all, or even the possibility of increased mortality risk.^{13,14,15,16,17}

These tocilizumab trials varied considerably in size, study design and subject illness severity; early trials in particular were underpowered to detect differences in death rates between groups, or excluded critically ill patients.¹⁸ After consideration of all the data, the National Institutes of Health’s (NIH) COVID-19 Treatment Guidelines Panel has recommended the use of tocilizumab in combination with dexamethasone solely for certain hospitalized COVID-19 patients exhibiting rapid respiratory decompensation within the first three days of admission.¹⁹ As more evidence comes in, it is becoming increasingly apparent that this highly targeted IL-6 inhibitor offers limited benefit against the multifactorial cytokine storm phenomenon that accounts for severe COVID-19-related complications, ICU admissions and deaths.

Other narrowly targeted immunomodulators continue to be evaluated as potential treatments to limit cytokine storm-mediated injury, among which are interferons, IL-1 inhibitors and Janus kinase inhibitors, including baricitinib. With the exception of baricitinib in combination with remdesivir, which are narrowly approved under an emergency use authorization in hospitalized patients for whom corticosteroids cannot be used, there are currently insufficient data to support their use.²⁰

The physiologic inflammatory process that helps clear infections involves a vastly complex interplay between cytokines and cellular immune elements, as does the pathophysiologic process leading to overproduction of inflammatory cytokines in response to a severe, overwhelming or prolonged infection. Thus, it should come as no surprise that highly specific immunomodulators are of modest or no value as means to downmodulate cytokine storm and resulting organ damage. 

Multimodal Immunoregulatory Actions Make IVIG Unique

While there may be no “magic bullet” to treat cytokine storm, one widely used immunomodulatory agent in particular — polyclonal intravenous immune globulin (IVIG) purified from healthy donor plasma — is distinguished by the simple fact that it is anything but a narrowly targeted treatment. More than two decades ago, immunologists first proposed the therapeutic effect of IVIG may be related to its demonstrated ability to reduce levels of multiple proinflammatory cytokines.^21,22 While the mechanisms involved remain largely obscure, the potent immunomodulatory activity of high doses of these human IgG concentrates is exploited to treat diverse autoimmune inflammatory disorders ranging from chronic inflammatory demyelinating polyneuropathy to dermatomyositis to Kawasaki syndrome.

Past studies suggest immunoregulatory IgG antibodies address the pathophysiology of cytokine storm in COVID-19 patients through a number of mechanisms, including:

• Direct F(ab)’2-mediated neutralization of inflammatory cytokines, chemokines and complement fragments;

• Inhibition of innate immune cell activation and secretion of proinflammatory mediators;

• Scavenging of complement fragments and inhibition of complement system activation;

• Functional blockade of Fc receptors required to activate immune complexes; and

• Saturation of endothelial FcRn, resulting in increased clearance of pathogenic IgG and other antibodies.

In addition to attenuating excessive production of pathogenic inflammatory cytokines and chemokines, immunoregulatory IgG in standard IVIG may also prevent tissue injury by downregulating overactive mononuclear macrophages, dendritic cells, natural killer cells and lymphocytes.²³ 

Expanding Evidence of IVIG Efficacy vs. Cytokine Storm

Prompted by this understanding, Chinese physicians at the Wuhan Third Hospital were the first to report on the use of IVIG to treat COVID-19 in 58 critically ill adult patients with pneumonia admitted to the ICU between January and February 2020.²⁴ In addition to supplemental oxygen, antiviral agents, antibiotics and other standard therapies, patients received 20 grams of IVIG daily when the absolute lymphocyte count fell to less than 0.5 x 109 per liter. In a post-hoc analysis, patients were divided into two groups: those first given IVIG ≤48 hours after admission (n=30) and those first started on IVIG >48 hours after admission (n=28). IVIG administration was delayed by just over one day in the >48 hour group compared to the ≤48 hour group (2.7 vs. 1.6 days).

Altogether, 23 of the 58 patients died within 28 days of admission: seven (23.3 percent) in the ≤48 hour and 16 in the >48 hour IVIG treatment groups. Survivors received their first IVIG infusion a day earlier (2.26 ± 0.20 days) than nonsurvivors (3.39 ± 0.32 days). Both hospital and ICU length of stay was about one-third shorter in the ≤48 hour-treated group. Consistent with the significant difference in mortality, just two patients started on IVIG within the first 48 hours (6.7 percent) required mechanical ventilation, compared to nine patients who started on IVIG more than 48 hours after admission (32.1 percent). While not a proof of IVIG efficacy against COVID-19 cytokine storm, these findings do imply that — if administered early enough — IVIG could potentially blunt possibly lethal hyperinflammatory injury to lungs and other vital organs. 

A second larger retrospective study in 325 Chinese COVID-19 patients examined IVIG use compared to nonuse during that same time frame in early 2020.²⁵ After adjusting for multiple variables (e.g., age, comorbidities, CRP level and baseline clinical status), there was a significant difference in 28-day mortality favoring patients who received IVIG. And strikingly, in the cohort of 174 patients who received IVIG, both higher dose and earlier administration were associated with significantly lower mortality (Table 1).

But further analysis revealed two additional patterns: 

1) A survival benefit of IVIG therapy was apparent only in the subset of patients with critical-stage disease with a high risk of death: 28-day mortality was sharply lower in critical-stage patients given IVIG versus those not given IVIG (27 percent vs. 53 percent; P = 0.009) but was not different for patients classified as “severe” with a low mortality risk (3 percent in both IVIG and non-IVIG subgroups). 

2) In critical-stage patients, higher IVIG dose was associated with lower mortality: 27 percent for the subgroup receiving more than 15 grams per day, compared with 68 percent for patients receiving ≤15 grams per day.

A third early retrospective study sought to answer whether IVIG therapy might offer clinical benefit in nonsevere hospitalized COVID-19 patients without signs of respiratory distress (respiratory rate <30/minute, pulse oxygen saturation >93 percent at rest) or organ failure.²⁶ Using propensity score matching, outcomes in 45 nonsevere COVID-19 patients treated with IVIG were compared with outcomes in 90 untreated nonsevere patients. There were no significant differences in any outcomes, including risk of progression to severe disease (6.6 percent vs. 3.3 percent), deaths (1 vs. 0) and length of hospital stay (14 days vs. 13 days). “No benefit was observed with IVIG treatment beyond standard therapy in the treatment of nonsevere patients with COVID-19,” the investigators concluded. This finding is entirely consistent with hypotheses that the immunoregulatory properties of IVIG can be expected to benefit only more severely affected patients experiencing or at imminent risk for cytokine storm and consequent immune-mediated lung and other organ injury.

A number of case series, case-control studies and small randomized, controlled trials (Table 2) have subsequently added to the body of evidence suggesting administration of high-dose IVIG therapy can importantly reduce mortality, reduce serious morbidity and shorten recovery time in severely ill hospitalized COVID-19 patients.

Next: Answers from Definitive IVIG/COVID-19 Trials

Intent on delineating whether and in whom high-dose IVIG can be beneficial, several major IVIG manufacturers have organized prospective clinical trials that randomize severely ill COVID-19 patients to receive high-dose IVIG or placebo infusions, or alternatively randomly assign patients to high-dose IVIG plus standard medical treatment (SMT) or SMT only.

Subject enrollment has been completed for a multinational Phase III, fully-blinded randomized trial sponsored by Octapharma to compare high-dose Octagam 10% IVIG against placebo in 208 hospitalized COVID-19 patients with severe disease progression.²⁷ Active treatment group subjects received 2 g/kg of IVIG in four divided doses over four consecutive days. A six-point clinical status scale that includes hospital discharge, increasing levels of hospital treatment intensity and death will be applied to assess the proportion of subjects who improve or are stabilized at days 7 and 14. Results of this trial are anticipated shortly.

Grifols is coordinating two Phase II pilot studies targeting different COVID-19 patient populations. Ten participating centers in Spain very recently completed enrollment and randomization of 100 patients to receive SMT plus 2 g/kg of Flebogamma DIF IVIG over four days to five days, or SMT alone.²⁸ Primary outcome measures include 1) death or ICU admission and 2) dependency on high-flow oxygen devices or mechanical ventilation at day 29. 

Fifteen U.S. sites participating in the second Grifols-sponsored study are currently enrolling 100 COVID-19 patients requiring ICU admission, who are being randomized to receive either 2 g/kg of GAMUNEX-C plus SMT, or SMT alone.²⁹ Among the key outcome measures, all through day 29, are all-cause mortality, time to ICU discharge, duration of any oxygen use and change from baseline in Sequential Organ Failure Assessment (SOFA) score. Subject enrollment is projected to be completed this summer.**

While we await the findings of these trials, the NIH COVID-19 Treatment Guidelines Panel continues to recommend against the use of IVIG to treat COVID-19. At this writing, that NIH panel recommendation had not been updated since July 2020.³⁰ Some clinicians battling to save their severely ill COVID-19 patients with clear indicators of cytokine storm might nevertheless find themselves contemplating IVIG therapy given 1) the volume and consistency of evidence supporting the efficacy of IVIG that has yet to be examined by this NIH panel, 2) an absence of serious safety signals with administration of high-dose IVIG and 3) the paucity of proven available treatments.

IVIG has a long history of being overlooked as a prospective treatment for immune-mediated disorders; many for which IVIG is now commonly used weren’t discovered until decades after its initial approval in 1981 for the treatment of immune thrombocytopenic purpura. Forty years later, new clinical applications continue to emerge for what is, in essence, a concentrate of the normal humoral immune system. And given the highly encouraging published evidence thus far, it would be foolish to bet against IVIG as a potentially important new treatment for patients with severe COVID-19.