In Case of a Shortage: Strategies to Conserve the Immune Globulin Supply

 SINCE MARCH of last year, the COVID-19 pandemic has forced cancellations of thousands of blood drives and dissuaded many would-be donors from visiting their local community blood center. While the resulting drop in the blood supply has been mitigated in part by public appeals for blood donation, millions of Americans are well-acquainted by now with the primary tactic hospitals have employed to ensure adequate inventories of blood to meet critical and emergency needs: cancellations of elective surgeries. At the peak of the pandemic last year, an estimated 340,000 elective surgeries were cancelled each week,¹ many of which would have required transfusions of blood that blood banks did not have on hand. 

U.S. donations of plasma intended for further processing into polyvalent immune globulin (IG) and other therapeutic proteins have similarly been heavily impacted by the pandemic. But while hospitals have been able to contract their blood usage by simply postponing elective surgeries until supplies improve, simply cancelling or deferring IG treatments for patients who require it for humoral immunodeficiency disorders or a host of severely debilitating autoimmune or inflammatory diseases is not an option. What, then, can be done in the event of a severe shortage of IG products, whose production is entirely reliant on a continuous supply of IgG-rich plasma donated at more than 800 dedicated U.S. collection facilities? 

At this writing, there is no IG shortage, and the potential for a shortage situation remains hypothetical. Despite months-long periods of sharp declines in plasma collections last year, both intravenous IG (IVIG) and subcutaneous IG (SCIG) have generally remained in good supply over the more than yearlong course of the pandemic. Unquestionably, cancelled clinic visits that would otherwise have generated diagnoses and new orders for IG have played a role. But the real answer to this medical challenge is related to the complexity and protracted length of time required to process plasma into IgG and other therapeutic proteins.* 

According to the Plasma Protein Therapeutics Association, between seven months and 12 months are required to manufacture a single batch of IG, from the pooling of thousands of donor units to shipment of the product in its final container form. In addition, plasma units are quarantined in a frozen state for a minimum of 60 days before they are released for manufacture.² 

How does that long production time frame affect IG supply in the context of the current COVID-19 pandemic? The highly simplified model in Figure 1 tracks just a few batches of plasma, each on its roughly one-year journey to become an IVIG or SCIG product. We see in Figure 1 that IG delivered in 2020 — the first year of the pandemic — was produced from plasma collected a year earlier in 2019, well before the COVID- 19 crisis came along to dissuade donors from visiting their local plasma collection center. 

But starting in March 2020, pandemic-related concerns and public orders restricting mobility resulted in a substantial drop in donations. By mid- May 2020, some reports suggest that total volume was down as much as 30 percent, according to Patrick Schmidt, CEO of FFF Enterprises, a leading plasma products distributor. “There was a bit of a resurgence in donations over the summer when cases were down, but now we’re in a much more difficult time, and donations will likely decline again,” he added in a recent interview.³

Those shortfalls in plasma collections in 2020 will directly translate into lower IG production as we advance through 2021. Again, however, other mitigating factors could minimize or entirely prevent an IG shortage, the most important of which is constrained IG utilization as some patients on chronic IG therapy may skip or delay their outpatient infusion visits, and others who would otherwise have been prescribed IG therapy put off scheduling appointments to see a specialist. 

Whether ongoing plasma supply shortages ultimately result in IG supply shortages remains to be seen, but the prospect itself returns us to the original question: What can be done in the circumstance of an IG undersupply — without compromising patient care? 

Dosing with Ideal or Adjusted Body Weight Spares IVIG 

Infused IVIG is known to mainly accumulate in blood plasma, with much less distribution in body tissues and minimal distribution in fat tissue.⁴ As a consequence, when an overweight or obese patient (generally defined as a body mass index [BMI] ≥ 30 kg/m2) is dosed with IVIG in accordance with his or her actual body weight (ABW), the resulting serum IgG level is elevated above that of a nonoverweight patient who receives the same weight-based dose. As pointed out in a statement by the Society of Critical Care Medicine, “obese patients who are dosed at ABW may be put at additional risk for adverse reactions due to excess plasma concentration.”⁵ Partly for this reason, IVIG clinical trials typically exclude individuals with a BMI above a specified threshold. 

A report by a large U.S. immunology clinic providing chronic IVIG therapy to obese and nonobese primary immune deficiency (PI) patients appears to validate this effect of excess adiposity on IgG serum levels. As a result of this clinic’s general policy to “cap” monthly dosage, the mean monthly IVIG dose for patients with a BMI ≥30 kg/m2 was 14 percent lower than the monthly dose for those whose BMI was under 30 kg/m2 (0.54 g/kg versus 0.63 g/kg). Yet the mean serum IgG levels for obese and nonobese patients were about the same (882.2 mg/dL versus 903.4 mg/dL).⁶ 

For overweight and obese patients, many academic medical centers now utilize either a calculated ideal body weight (IBW) or adjusted body weight (adjBW) to arrive at an IVIG dose. Figure 2 provides examples of how ABW may be converted to either an IBW or an intermediate adjBW as the basis for IVIG dosing, an approach sometimes referred to as “precision dosing.” A simple patient height-based equation — the Devine Formula — is most commonly used to calculate patient IBW,⁷ which can be further adapted to specify an adjBW that falls between ABW and IBW. The Ontario Regional Blood Coordinating Network provides a widely referenced online tool, using inputs of patient height and weight, to generate IBW, adjBW (called “dosing weight”) and IVIG dose calculated using the dosing weight.⁸ 

adjBW or IBW-based IVIG dosing is a standard practice in a number of countries, including Canada, Australia and the United Kingdom.^9,10 According to the most recent survey by the U.S. Centers for Disease Control and Prevention (CDC) in 2016, 72 percent of U.S. adults are now classifiable as overweight or obese, up significantly from 64 percent in 1999.¹¹ Consistent with these U.S. figures, a group of Canadian provinces reported that, in fiscal 2019, adjBW was utilized to reduce administered dosages in 64 percent of all patients (817/1,270) receiving IG therapy. This use of adjusted “dosing body weight” translated into 14 percent overall savings in IG grams and associated cost. 

Pharmacists at Brigham and Women’s Hospital applied IBW-based dosing for all inpatient IVIG orders over a period of one year.¹² For the majority of cases (142/265; 54 percent), IVIG was prescribed for hypogammaglobulinemia with recurrent infections in oncology and bone marrow transplant patients. The mean patient IBW and ABW were 63.3 ± 10.5 kg and 77.3 ± 9.2 kg, respectively. Using IBW for dosing, a total of 15,383 grams of IVIG was dispensed over the one-year period, which was 3,880 grams or 20 percent less than the gram total had dosing been based on actual patient body weight. 

In a retrospective analysis of all IVIG doses administered over a recent five-year period, investigators at MD Anderson Cancer Center concluded that use of an adjBW-based dosing formula would have yielded a 24 percent reduction in dispensed IVIG grams.¹³ Astonishingly, their calculations found that use of IBW would have reduced dispensed IVIG grams by nearly 36 percent. “IVIG dosing optimization through the use of alternative dosing weights represents a significant source of waste reduction and cost reduction,” the study authors concluded. 

An obvious presumption behind these IVIG dose-sparing strategies is that circulating IgG levels and bioavailability that roughly approximates a standard dose in lean individuals will provide similar therapeutic benefit. A team at the University of North Carolina Medical Center put this question to the test with a lookback at actual patient outcomes data. Of 209 consecutive IVIG infusion encounters in adults with hematologic malignancies, 125 were dosed traditionally by ABW, while 84 others were dosed in accordance with an IBW- or adjBW-based formula. No differences were seen in 30-day infection rates between the precision dosing and the traditional ABW-based dosing methodology (15.5 percent versus 16 percent, respectively); 60-day infection rates were similar as well. 

IG dosing based on IBW or ABW has particularly been embraced by hospitals as a significant cost-saving opportunity. But in the potential context of a national IG shortage situation, its value as a safe and effective means to conserve IG applies equally for the roughly 50 percent of patients who receive their treatments at home or in other nonhospital settings. 

Titrating IG Dose for Each Patient 

While oral and most injectable medications are typically prescribed at the dosage recommended in the package insert, it makes sense to individualize the dosage of IG when it is used as chronic immunomodulatory or IgG replacement therapy. For most patients on chronic IG therapy, the recommended dosage should serve as a starting point. 

Each patient metabolizes infused IgG at a different rate. In particular, when IVIG or SCIG is prescribed as long-term replacement therapy for new patients with a PI, the dosage can be initially adjusted to achieve the desired serum IgG trough level. Prescribing information for most IVIG and SCIG products further recommend dosage adjustments as needed to attain an optimal protective response. This practice, as opposed to simply prescribing a “standard” dose that turns out to be effective for the patient, can help minimize wastage of excessive IG, reduce the likelihood of side effects and shorten infusion time or frequency of infusion sessions. 

When the immunomodulatory properties of IG are exploited to treat disabling chronic immune neuropathies, such as chronic inflammatory demyelinating polyneuropathy (CIDP) or multifocal motor neuropathy, clinicians most commonly like to continue with the standard maintenance dose (e.g., 1 g/kg for CIDP) and increase the time interval between infusions to find the longest interval that will maintain remission without relapse. This strategy may allow discontinuation of IVIG treatment altogether for some patients who remain in clinical remission.¹⁴ 

A special consideration with CIDP is the unfortunately commonplace misapplication of this diagnosis, followed by inappropriate prescribing of high-dose IVIG therapy. Clinical and electrodiagnostic evaluations of 59 consecutive patients diagnosed with CIDP and referred by community neurologists to an academic center found 47 percent of them failed to meet diagnostic criteria for the disorder.¹⁵ A separate expert assessment of case records for 248 patients with presumptive immune neuropathies who received home-based IVIG treatment determined only 32.2 percent actually had an immune neuropathy and were appropriate candidates for IVIG therapy. Another 46.4 percent had neuropathies that were not immune-mediated.¹⁶ Consistent with these findings, just 36.7 percent of cases with reviewable records actually responded to IVIG therapy. Plainly, there is an opportunity to avoid wastage of IVIG by first subjecting potential treatment candidates to more stringent diagnostic assessments. 

Prioritizing Better Supported Use 

In the commonplace circumstance when one or more IG product brands are temporarily unavailable, providers are well-accustomed to being asked to switch affected patients to a different brand in good supply. Separately, challenges securing and processing enough additional plasma to keep pace with 8 percent to 9 percent annual demand growth¹⁷ have created intermittent shortages that have affected many providers over the last several years. But we have never experienced the kind of severe, protracted IG supply shortage situation that could potentially arise from the pandemic-caused decline in plasma collections that began more than a year ago in March 2020. A scenario of this nature could require pharmacists and physicians to make many difficult decisions about which patients do and do not receive IG therapy. 

To rationalize IG utilization in the context of budgetary or supply constraints, a number of countries with national healthcare systems have formalized this process, assembling expert panels that review and grade the available evidence supporting IG use across a wide spectrum of clinical indications.^18,19 The UK’s Clinical Guidelines for Immunoglobulin Use, for example, employs a color-code scheme to assign a priority to each clinical use (Figure 3), and whether IG is recommended for short-term or long-term use, or both. Particularly helpful is the “blue” prioritization, which identifies clinical indications for which other treatment options are available and whether the use of IG “should be modified in times of shortage.”²⁰ 

In the U.S., these and other helpful published guidelines can assist individual provider organizations in making informed decisions about which patients should receive priority for IG therapy in the event of a severe shortage. The American Academy of Allergy, Asthma & Immunology, for example, has conducted a comprehensive review of evidence that assigns indications to one of four categories: definitely beneficial, probably beneficial, may provide benefit and unlikely to be beneficial.²¹ 

Fortunately, many providers, including large tertiary care hospitals in particular, have already visited this issue to address past shortage situations. “We prioritize patients with chronic immune deficiency, life-threatening conditions such as immune thrombocytopenic purpura, Guillain-Barré syndrome and Kawasaki disease, versus indications where there are effective alternatives — for example, multiple sclerosis,” noted the Mayo Clinic’s vice chair for pharmacy supply solutions Eric Tichy, PharmD, in a recent interview with Pharmacy Practice News.²² 

It Comes Down to the Plasma 

Patient advocacy organizations and plasma collection centers from coast to coast have boosted appeals for donors during the ongoing pandemic, reminding prospective donors of the value of their gift of plasma, and providing assurances that donating plasma is safe. The Immune Deficiency Foundation, for example, has launched an initiative called “PlasmaHero” to educate the general public about the critical need for plasma and to connect potential donors with resources to get started.²³ All indications suggest these efforts are helping to convince more donors to return or step up to donate plasma for the first time. 

Yet the concern remains that many months of sharply lower plasma collection activity already caused by the COVID-19 pandemic may yet impact IG supply as we continue into 2021. Without question, the best and surest way to avert or at least mitigate an impending IG shortage tomorrow is to take advantage of measures we know from experience can help to conserve more of this precious product today.