Fact or Fiction: Debunking the Myths Surrounding IG Therapy Improves Patient Outcomes

by Luba Sobolevsky, PharmD, IgCP, Rachel Colletta, BSN, CRNI, IgCN and Amy Clarke, RN, BSN, IgCN

IMMUNE GLOBULIN (IG) is made from pooled plasma collected from thousands of donors. It contains antibodies against a broad spectrum of bacteria and viruses, and it is used primarily to treat three categories of illnesses: primary immune deficiencies, autoimmune neuromuscular disorders and certain rheumatologic conditions. Historically, the first intravenous IG (IVIG) therapy was approved in 1981 to treat primary humoral immunodeficiency disorders, and in 2006, the first subcutaneous IG (SCIG) therapy was approved. Today, a growing number of patients are treated with IG, and the number of IG products and routes of administration continue to evolve. Yet, while patients treated with IG experience healthier lives, many may have misconceptions about the products, how they are administered and the reactions they can cause.

Myth or Fact? IG Products Are Interchangeable

Myth: IG products are not interchangeable. While all products contain similar amounts of IgG antibodies, the similarities end there. Brands of IG can differ in IgG monomer, dimer and aggregate concentrations. They also differ in concentrations of IgA and IgM (Figure 1). Stabilizers, additives, sodium content, osmolarity and levels of impurities vary from product to product. Because of these differences, IG products cannot be used interchangeably or be mixed together.

Product differences should be considered when choosing the ideal product for each patient. In addition to product differences, patient differences such as comorbidities, tolerability, history of product use and patient lifestyle must be taken into account when choosing a product and route of administration.

Because products are tolerated differently by individuals, first doses of any product should be administered with caution. This is true even when a patient switches from one brand of product to another.

The IG clinician’s role is to assess product tolerability and communicate with the healthcare team to ensure the patient has a safe and positive infusion experience.

Potential adverse drug reactions (ADRs) are listed in manufacturers’ labeling, which considers both ADRs noted during clinical trials and those seen with all IG products in general.

Overall, IG therapy is safe and well-tolerated in most patients, and clinical efficacy of all products is comparable. However, all IG products contain boxed warnings. IVIG products contain boxed warnings for thrombosis and renal dysfunction/acute renal failure (ARF), whereas SCIG and facilitated SCIG (fSCIG) products contain only boxed warnings for thrombosis (see A History of the Thrombosis Boxed Warning). Therefore, it is imperative a thorough clinical assessment is conducted prior to starting care, and there is astute monitoring during the infusion and post-infusion follow-up.

Thrombosis. Risk factors for thrombosis include advanced age (but not specified); prolonged immobilization; hypercoagulable conditions (easy/excessive blood clotting), which may be inherited (e.g., Factor V Leiden) or acquired (e.g., cancer, certain cancer medications, obesity, HIV/AIDS, pregnancy); history of venous or arterial thrombosis; use of estrogen; indwelling vascular catheters; hyperviscosity conditions, including hypergammaglobulinemia markedly increased triglycerides, cryoglobulinemia, paraproteinemia (e.g., macroglobulinemias, monoclonal gammopathy of undetermined significance [MGUS], multiple myeloma); and cardiovascular risk factors. However, thrombosis may occur in the absence of known risk factors.

Mitigation strategies for thrombosis include:

• Administering at the minimum dose feasible (when there is no specific recommendation, large doses can be divided over several days or administered on alternate days)

• Administering at the minimum infusion rate feasible (some brands include no recommendation and other brands recommend 3 mg/kg/minute maximum to 4 mg/kg/minute maximum)

• Ensuring adequate hydration in patients before administration (requirements differ between adult and pediatric patients)

• Monitoring for signs and symptoms of thrombosis (for example, deep vein thrombosis symptoms include lower-leg swelling and pain in knees; pulmonary embolism (PE) symptoms include shortness of breath/pain with breathing and chest pain; myocardial infarction symptoms include chest pain; and transient ischemic attack/cerebrovascular accident symptoms include confusion, slurred speech, drooling and loss of consciousness)

• Assessing blood viscosity in patients at risk for hyperviscosity

• Educating patients about the signs and symptoms of thrombosis

It should be noted that anti-thrombotic therapy concurrent with IVIG should be considered for patients at high risk of thrombosis.

Renal dysfunction and acute renal failure (ARF). Renal dysfunction, ARF, osmotic nephrosis and death may occur with IVIG products in predisposed patients. Renal dysfunction and ARF occur more commonly in patients receiving IVIG products containing sucrose. However, since the last sucrose-containing product was withdrawn from the market in 2018, renal dysfunction and ARF could occur with any brand.

Risk factors for renal dysfunction and ARF include any degree of pre-existing renal insufficiency, diabetes mellitus, age older than 65 years, volume depletion, sepsis, paraproteinemia (e.g., macroglobulinemias, monoclonal gammopathy of undetermined significance, multiple myeloma) and patients receiving known nephrotoxic drugs.

Package insert recommendations for mitigation strategies for renal dysfunction and ARF vary among brands, with some including more instruction than others and some recommendations described outside the boxed warning. Strategies include:

• Administering at the minimum dose feasible (same as thrombosis)

• Administering at the minimum infusion rate feasible (same as thrombosis)

• Administering at the minimum concentration available (this pertains to only two brands)

• Ensuring adequate hydration in patients before administration (same as thrombosis)

• Periodic monitoring of renal function and urine output in patients judged to be at increased risk of developing ARF

• Assessing renal function, including measurement of BUN and serum creatinine, before the initial infusion and at appropriate intervals thereafter

• Considering discontinuation if renal function deteriorates

Myth or Fact? Anaphylaxis Is a Common Occurrence with IG Therapy

Myth: Anaphylaxis is not a common occurrence with IG therapy. In fact, true anaphylactic reactions to IG therapy are rare.

All IG brands contain IgA, and it is possible for individuals with IgA deficiency to develop anti-IgA antibodies and anaphylactic reactions after administration of IgA-containing products. Anaphylactic reactions are IgE-mediated and involve the release of mediators from tissue mast cells and peripheral blood basophils. Anaphylactic reactions present as an early onset, acute set of symptoms and are considered medical emergencies.

Anaphylaxis can occur with any IG infusion, so the IG clinician must have clinical expertise in managing these reactions, including the use of epinephrine (intramuscular or subcutaneous), oral or parenteral diphenhydramine (intravenous or intramuscular), corticosteroids, IV solution and supplies (syringes, needle). An anaphylaxis kit should be readily available when every dose is administered, and the patient’s vital signs must be monitored. And, since anaphylaxis can occur with any infusion no matter how long the patient has been receiving IG therapy, patients should not self-infuse or be left alone for any period of time during the infusion.

After anaphylaxis symptoms resolve, the decision to restart an infusion should be made by the prescriber, patient, nurse and pharmacist. Mitigation strategies to prevent anaphylaxis include pretreatment with an antihistamine and corticosteroid, choosing another IVIG or SCIG brand if it is not IgA autoantibody-related or, if it is IgA autoantibody-related, switching to products containing lower levels of IgA or SCIG therapy.

Much more common than an anaphylactic reaction is an anaphylactoid reaction. Anaphylactoid reactions are similar in presentation to anaphylactic reactions since patients experience shortness of breath and chest tightness. However, these symptoms are much more gradual in onset and severity. Anaphylactoid reactions generally occur within the first half of the infusion and will dissipate with no intervention once the infusion has ended. And, because anaphylactoid reactions are not IgE-mediated, patients will typically experience hypertension rather than hypotension.

Anaphylactoid reactions may be caused by IgG aggregates or impurities not removed during the manufacturing and purification processes; however, the true cause of these reactions remains unknown. It is important for clinicians to understand these differences and be prepared to treat patients accordingly.

Serious ADRs include aseptic meningitis, hemolytic anemia and transfusion-related acute lung injury (TRALI).

Severe aseptic meninigitis generally occurs after an infusion and lasts hours to days. The cause is IG-induced spinal cord inflammation, and it is often described as severe and debilitating. Frequently, it is accompanied by nuchal (nape of the neck) rigidity, drowsiness, photophobia, painful eye movements and nausea (with or without vomiting). Cerebral spinal fluid studies may show increased white blood cell count and protein with a negative culture.

Risk factors for aseptic meningitis include high doses of IG, rapid infusion rate, dehydration and a history of migraines. Pretreatment is generally ineffective; however, there have been some reports of success with IV corticosteroids, IV hydration and antimigraine medication. Treatment may require aggressive pain management.

Mitigation strategies for aseptic meningitis include:

• Reducing the daily dose by dividing over several days

• Alternating days of dosing

• Reducing the maximum infusion rate

• Switching to an IVIG 5% product

• Switching to a different IVIG brand or to SCIG

Hemolytic anemia occurs when there is severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation (a blood clotting disorder) caused by a destruction of red blood cells due to anti-A and anti-B blood type antibodies.

Risk factors for hemolytic anemia include non-O blood types, underlying inflammatory states, immune-mediated disorders and high IVIG doses (e.g., greater than 2 grams/kg, single or divided).

Signs and symptoms of hemolytic anemia generally present within days or weeks and may include fatigue (mild hemolysis), dark urine, jaundice of skin or eyes, heart murmur, increased heart rate and enlarged spleen/liver, which may be life-threatening and require blood transfusions. Therefore, patients should be educated about the signs and symptoms and when to call the prescriber.

Since there is little published evidence about the prevention of hemolytic anemia, mitigation strategies should include:

• Understanding the patient’s blood type

• Administering at the slowest rate feasible

• Reducing the daily dose, dividing the dose over several days or alternating days

• Considering an Hgb/HCT test prior to IVIG within approximately 36 hours and in seven days to 10 days if the patient is high risk

TRALI is a rare but potentially fatal complication of receiving blood products. It causes severe respiratory distress, pulmonary edema (non-cardiogenic), hypoxemia (below-normal level of oxygen in the blood), normal left ventricular function and fever. Symptoms typically appear within one hour to six hours following IVIG. It may be managed using oxygen therapy with adequate ventilatory support. There are no particular risk factors or mitigation strategies.

Myth or Fact? ADRs Can’t Be Mitigated

Myth: ADRs can be mitigated. These reactions are generally related to factors such as the rate of infusion, the patient’s hydration status, patient comorbidities (e.g., history of migraine) and product choice. Whenever possible, the goal should be to prevent ADRs from occurring, which can usually be accomplished by patient education and proper product selection and administration.

Managing ADRs starts with a risk assessment performed by the pharmacist prior to the start of therapy to determine what, if any, comorbidities exist, as well as the patient’s history with IG therapy and with previous products.

Product and route selection are the first steps in mitigating ADRs. Patients tolerate products differently, so there is not a one-size-fits-all solution for product selection. Prior history, comorbidities and patient lifestyle factors should be considered.

A well-hydrated patient runs a lower risk of experiencing infusion-related ADRs. Patients should be instructed to begin hydrating one day to two days before the infusion, and hydration should be continued throughout the infusion and into the next day. If patients are not able to consume the amount of fluids needed to fully hydrate, IV hydration may be used as a supplement.

Premedications may be administered as needed, so patients should be assessed for their need for analgesic, antihistamine, antiemetics, etc.

Customizing the infusion rate to patient tolerability is critical. Since most ADRs are related to rate of infusion, a three-step ramping process should be used for every infusion. If ADRs occur, the infusion should be stopped and restarted at the previous infusion rate when symptoms subside. Remember that infusion rates vary from patient to patient and should be reassessed with each infusion.

Effective and frequent communication with the healthcare team is imperative. Patients should be encouraged to report any ADRs so appropriate intervention can be taken. Patients should not have to manage severe ADRs during and after their infusions.

Common mild to moderate IVIG infusion-related reactions include headache (most common) often occurring during the infusion due to mild/moderate blood pressure changes; diarrhea, fatigue, low-grade fever, nausea and other flu-like symptoms, which may last up to 72 hours and can be treated symptomatically; rash/hives; and blood pressure changes. Methods to mitigate these reactions include:

• Stopping the infusion until symptoms resolve, and resuming at a slower rate (recommended)

• Slowing the rate of infusion (may indicate the maximum tolerated rate for the product)

• Repeating ordered antihistamine and analgesic premedications if enough time has passed

A number of factors can contribute to SCIG ADRs. Infusion-related factors include a history of infusion reactions, first infusion, amount of drug infused, rate of infusion and dehydration. Patient-related factors include infection or fever at time of infusion, age, autoimmunity, comorbidities (i.e., diabetes, hypertension, cardiovascular disease) and smoking.

SCIG ADRs can be local or systemic (Figures 2 and 3). Local reactions are common, occurring in 75 percent of patients. These include immediate swelling and redness at the site of infusion that usually resolves within 24 hours to 48 hours and lessens with subsequent infusions. In fact, occurrence and severity has been shown to decrease over repeated SCIG administrations. Systemic reactions are rare, occurring in less than 1 percent of patients. These include back pain, migraine, diarrhea, fatigue, nausea, vomiting, rash and arthralgia (joint pain).

When experiencing local site reactions, the following management strategies can be tried:

• If tape sensitivity is suspected, use a skin preparation, different tape or change out the Tegaderm.

• Insert needle using a dry priming technique to decrease redness, itching and site reactions.

• Rotate needle insertion sites.

• Increase activity to help diffuse the product.

• Apply cold compresses 20 minutes on and 20 minutes off.

• Apply a cold topical anesthetic cream to the site, or use a device such as Buzzy.

• Slow or stop the infusion, and restart as the patient tolerates.

There may also be other issues related to SCIG infusions. If there is pain at the site of needle insertion, the needle length should be checked to ensure it is appropriate, and ice, a topical anesthetic or a device such as Buzzy can be used.

If there is leaking at the infusion site, the following should be checked:

• Needle dislodgement

• Needle length

• Subcutaneous tissue (is it adequate to absorb the volume of medication?)

• Infusion rate (is it too fast?)

If the infusion is taking too long, patency of tubing, rate of tubing and needle size should be assessed. Additionally, the site location should be assessed to determine if an additional site is needed. Lastly, the pump should be checked to ensure it is operating correctly.

If there is an acute or delayed infusion reaction (hives, swelling in the mouth or throat, itching, trouble breathing, fainting or dizziness), the infusion should be stopped and the infusion reaction protocol (antinuclear antibody-orders) should be initiated. Also, patients should contact their healthcare provider or emergency medical service if symptoms occur during self-administration.

Importantly, for each infusion, it should be checked and documented that the right drug and dose is being administered to the right patient using the correct route and duration.

Myth or Fact? Maximum Infusion Rates Vary from Patient to Patient

Fact: Maximum infusion rates do vary from patient to patient. IG infusions are titrated stepwise to a maximum rate tolerated by the patient and per the prescribing information, prescriber’s orders and organizational policies. Other factors that may impact the maximum infusion rate are the patient’s hydration status and comorbidities. The IgNS Standards of Practice published by the Immunoglobulin National Society (IgNS) recommend using a minimum of three rate ramping stages. For patients at risk for renal dysfunction and thrombotic events, IG should be administered at the minimum infusion rate feasible and no greater than the maximum rate specified in each manufacturer’s current prescribing information. Maximum infusion rates may vary from infusion to infusion based on the patient’s state of health on the infusion day.

Similar to finding the patient’s ideal product, finding the patient’s personal maximum infusion rate is key to providing a positive infusion experience.

Myth or Fact? Long-Term IVIG Patients with No Adverse Reactions Do Not Require a Healthcare Professional to Monitor Infusions

Myth: Anaphylactic reactions can happen with any infusion, even in long-term patients with no history of adverse reactions. A patient who is experiencing an anaphylactic reaction will most likely not be able to manage the acute onset of symptoms.

Patient health status and lot-to-lot variability of IG products are a few of the reasons these reactions can occur at any time. IgNS recommends all IVIG infusions be monitored from start to finish by a competent healthcare clinician.

Editor’s note: This article was prepared from a presentation delivered by the authors at the 2021 Immune Deficiency Foundation National Conference.

LUBA SOBOLEVSKY, PharmD, IgCP, is executive director of the Immunoglobulin National Society (IgNS), RACHEL COLLETTA, BSN, CRNI, IgCN, is director of educational resources at IgNS and AMY CLARKE, RN, BSN, IgCN, is the national director of nursing practice at Optum Infusion Pharmacy.