Intravenous Administration

The recommended rates of IVIG infusion were determined in early studies using reduced and alkylated IgG. Such preparations caused rate-related side-effects in 50% of patients. Newer preparations are generally more tolerable, but significant side-effects such as thrombosis have been associated with higher rates of infusion. Manufacturers recommend starting rates of 0.5–1 mg/kg/min and increasing incrementally up to rates anywhere between 3.3 and 8 mg/kg/min. The FDA recommends that for patients at risk of renal failure, e.g. preexisting renal insufficiency, diabetes, age greater than 65 years, volume depletion, sepsis, paraproteinemia and use of nephrotoxic drugs, or patients at risk of thromboembolic complications, the dose should be gradually increased to a more conservative 3–4 mg/kg/min maximum.

Subcutaneous Immunoglobulin Administration (SCIG)

Berger et al first described the use of the subcutaneous (SC) route for immunoglobulin replacement therapy in 1980. It was reported as safe, well tolerated and effective in achieving adequate serum IgG levels. Although used successfully in several studies, it was not very popular because it was time consuming due to the slow rate of infusion (1–2 mL/hr). Home treatment with rapid subcutaneous infusion was studied more extensively in the 1990s and was demonstrated to be well tolerated, efficacious and resulting in fewer systemic side-effects than IVIG. A meta-analysis of SCIG vs IVIG efficacy and safety studies demonstrated a trend toward better infection control with SCIG (though not achieving statistical significance), along with improved patient quality of life and decreased systemic adverse events when compared with IVIG therapy. Higher and more stable trough levels have been seen with the subcutaneous administration of immunoglobulin, alleviating the fatigue and general constitutional symptoms patients have on IVIG toward the end of their 3–4 weeks dosing interval. The above qualities have made SCIG a viable alternative to IVIG for many patients, especially those with significant systemic adverse effects with IVIG.

When immunoglobulin is administered via the SC route, the dose is absorbed into the circulation and redistributed to the peripheral tissues more slowly than when given via the IV route. One study showed that SCIG infusions (100 mg/kg of a 16.5% preparation) reach a steady state after 6 months if given weekly, or in one week if patients are first loaded with IVIG or given daily SC infusions for 5 days, prior to their maintenance weekly SCIG.

In the USA a 20% immunoglobulin product for subcutaneous use is available and several 10% liquid products have both intravenous and subcutaneous indications ( Table 15-1 ). The FDA required a dose adjustment in SCIG licensing studies, such that the weekly SCIG dose results in a total serum IgG exposure (area under the curve [AUC] of serum IgG versus time) equivalent to that of previous IVIG treatment. Based on this AUC calculation, SCIG prescribing information recommends product-specific dosage increases of 37% to 53% when transitioning patients from IVIG to SCIG. However, Berger et al have recently shown that all US-licensed SCIG products have a similar bioavailability: 66.7% ± 1.8% of IVIG. They suggest that decreased bioavailability is a basic property of SCIG rather than the result of any manufacturing process or product concentration, and that dose adjustments are not necessary when switching from one SCIG product to another.

Several studies from the EU, where a 1 : 1 conversion from IVIG to SCIG is standard, suggest that a dose adjustment from IVIG to SCIG may not be necessary to achieve good clinical outcomes. In contrast, Haddad et al found that patients receiving SCIG doses that were 1.5 times higher than their previous IVIG doses had significantly lower rates of non-serious infections, hospitalization, antibiotic use and missed work/school activity, compared to patients that received SCIG doses identical to previous IVIG doses. When switching a patient from IVIG to SCIG, making a dosage decision based on trough serum IgG levels and the clinical response to therapy is preferable to only taking pharmacokinetic measures into consideration.

The technique of administering SCIG can be taught to most patients or caregivers to facilitate home self-administration. Infusions may be given anywhere from daily to weekly or biweekly via 1 to 6 sites, depending on the total amount infused and the amount that can be accommodated in a single site (a function of body mass index). Infusion sites are usually on the abdominal wall and inner thigh. Other sites may include posterior upper arms, flanks or below the buttocks. Before infusion is started, the lines need to be checked to ensure that there is no blood return. The rate of infusion of the various SCIG products is set initially at 15–20 mL/site/hr and may subsequently be increased up to 25–30 mL/site/hr, if no adverse reactions occur. A general guideline is 0.1–0.25 mL/kg/site/hr.

Rate-related Adverse Reactions

Most adverse reactions of IVIG are related to the administration of IVIG and are rate related. Common adverse events include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash and low-grade fever ( Box 15-3 ). More serious reactions include dyspnea, nausea, vomiting, circulatory collapse and loss of consciousness. Patients with more profound immunodeficiency or patients with active infections have more severe reactions. Some of these reactions have been shown to be related to the complement-fixing activity of IgG aggregates in the IVIG. In addition, the formation of oligomeric or polymeric IgG complexes can interact with Fc receptors and trigger the release of inflammatory mediators. These adverse reactions occurred with lower frequency (10–15%) and with less severity in more recent preparations of IVIG. These reactions most commonly occur in newly diagnosed patients with hypogammaglobulinemia and in those patients who have chronic underlying infections such as sinusitis and bronchitis. One possible etiology is the binding of the infused antibodies to pathogen component antigens of the underlying chronic infection or inflammatory process. In a large prospective study of 459 antibody-deficient patients by Brennan and colleagues of 13,508 infusions, the reaction rate was only 0.8%. There were virtually no severe reactions (0.1%).

Common reactions to IVIG, including fatigue, myalgia and headache, may be delayed and may last several hours after the infusion. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with a nonsteroidal antiinflammatory agent, e.g. ibuprofen (10 mg/kg/dose), acetaminophen (15 mg/kg/dose), diphenhydramine (1 mg/kg/dose) and/or hydrocortisone (6 mg/kg/dose, maximum 100 mg) 1 hour before the infusion may prevent adverse reactions. If the patient continues to have adverse effects from IVIG despite pretreatment and rate change, the physician should consider changing the route of administration to subcutaneous.

Aseptic meningitis can occur with large doses, rapid infusions and in the treatment of patients with autoimmune or inflammatory diseases. Interestingly, this adverse reaction rarely occurs in immunodeficient subjects. Symptoms, including headache, stiff neck and photophobia, usually develop within 24 hours after completion of the infusion and may last 3 to 5 days. Spinal fluid pleocytosis occurs in most patients. Long-term complications are minimal. The etiology of aseptic meningitis is unclear but migraine has been reported as a risk factor and may be associated with recurrence despite the use of different IVIG preparations and slower rates of infusion.

Renal Adverse Effects

Acute renal failure is a rare but significant complication of IVIG treatment. Histopathologic findings of acute tubular necrosis, vacuolar degeneration and osmotic nephrosis are suggestive of osmotic injury to the proximal renal tubules. Fifty-five percent of the cases were in patients treated for idiopathic thrombocytopenic purpura (ITP), and less than 5% involved patients with primary immunodeficiency. This complication may relate to the higher doses of IVIG used in ITP. The majority of the cases were treated successfully with conservative treatment, but deaths were reported in 17 patients who had serious underlying conditions. Reports suggest that IVIG products using sucrose as a stabilizer may carry a greater risk for this renal complication. Because of this, the infusion rate for sucrose-containing IVIG should not exceed 3 mg sucrose/kg/minute. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age greater than 65, sepsis, paraproteinemia and concomitant use of nephrotoxic agents. For patients at increased risk, monitoring blood urea nitrogen and creatinine before starting the treatment and periodically thereafter is necessary. If renal function deteriorates, the product should be changed to a nonsucrose-containing IVIG or to SCIG.

Anaphylactic Reactions

Anaphylactic reactions to IVIG infusions are relatively rare. IgE and IgG antibodies to IgA have been reported to cause severe reactions in IgA-deficient patients receiving intravenous gammaglobulin preparations. Because of these concerns, the prescribing information for current gammaglobulin products includes either a precaution or contraindication to usage in IgA-deficient patients. Several studies have shown that these patients that have reacted to conventional IVIG preparations could then go on to tolerate IVIG preparations containing very low concentrations of contaminating IgA. However, other studies have described patients with anti-IgA antibodies tolerating IgA-containing IVIG preparations without reaction. Therefore the clinical significance of anti-IgA antibodies, and the role that these antibodies play in cases of anaphylaxis to IVIG products, remains controversial.

Thromboembolic Events

All human immune globulin products currently licensed in the USA carry an FDA warning of the risk of thrombosis with this class of products. Local thromboses at infusion sites, deep vein thrombosis, pulmonary embolism, myocardial infarctions, transient ischemic attacks and stroke have all been reported following IVIG infusion.

Risk factors for the development of IVIG-related thrombosis include advanced age, prolonged immobilization, hypercoagulable conditions, history of thrombosis, supplemental estrogens, indwelling central vascular catheters, hyperviscosity and cardiovascular risk factors.

It has been suspected that these thrombotic complications were due to platelet activation and/or increased serum viscosity in patients receiving large doses of IVIG. Recently, one IVIG product’s increased risk for thromboembolic events has been shown to be due to high levels of activated Factor XI (FXIa). Concerns over FXIa-related thrombosis have led to changes in manufacturing techniques, removal of Factor XI/XIa using an adsorbent during the manufacturing process, and use of the thrombin generation assay to monitor procoagulant activity of immunoglobulin products.

Hemolytic Adverse Reactions

Because IVIG preparations are prepared from a large number of donors, IgG isohemagglutinins (antibodies against A/B blood group antigens) are present in these preparations. In non-O blood type recipients, anti-A and anti-B antibodies from the IVIG may react with red blood cells to cause asymptomatic Coombs positivity, or less commonly clinically significant hemolytic reactions, especially in those receiving high cumulative doses of immune globulin. Clinically significant hemolysis is very rare in licensing studies of IVIG for primary immune deficiency, using doses of 400–800 mg/kg. Currently all immunoglobulin products licensed in the EU and USA are required to contain anti-A and anti-B titers that are less than or equal to 1 : 64 by the direct agglutination test. Despite this, current products meeting these regulations are still implicated in cases of hemolysis, and strategies to address this issue of hemolysis are being pursued by the FDA. Some manufacturers are instituting steps such as the use of adsorbents to lower titers of anti-A and anti-B.

Infectious Complications

Hepatitis C virus (HCV) infection in patients receiving IVIG products was initially reported in experimental lots in Europe and the USA. HCV infection usually occurred in clusters associated with contaminated lots and specific manufacturing procedures. The clinical course of HCV infection in patients with immune deficiency is not well defined. Routine screening of plasma donors for hepatitis C RNA by reverse transcriptase polymerase chain reaction (RT-PCR) and the addition of a viral inactivation process in the final manufacturing step, e.g. treatment with solvent/detergent and/or pasteurization, has drastically reduced the risk of transmission of hepatitis C and other viruses. In addition to these approaches in donor and plasma screening and testing, new innovative steps have been incorporated during the manufacturing process that include viral inactivation and viral removal stages. Some of the more common processes include solvent-detergent treatment of the final IVIG product to destroy potential lipid-envelope viruses, incubation at low pH, pasteurization, caprylate treatment and viral removal steps with depth filtration and nanofiltration. In aggregate, all these steps lead to a potential removal of 10–20 log ₁₀ reduction values (depending on the virus). Thus, today’s IVIG products are considered safe from a number of potential viral pathogens that were of concern in the early and mid 1990s. However, one potential group of pathogens that are still of potential concern are prions, which can cause transmissible spongiform encephalopathy, a fatal degenerative disease of the brain. IVIG manufacturers have recognized prion-mediated disease as a potential problem and have initiated testing and IVIG purification and treatment steps (e.g. nanofiltration) to address this issue.

Reactions to Subcutaneous Immunoglobulin

In general, the SCIG route has been remarkably free from severe systemic reactions. In contrast, the majority of patients do experience local site reactions at some point during SCIG therapy, with symptoms of swelling, soreness, warmth, redness, induration, pruritus and/or bruising. Most of these local reactions last for less than 48 hours, and the severity and frequency of local reactions decrease as the patient continues SCIG therapy.