Pediatric Common Variable Immunodeficiency Medication

Replacement Therapy with Human Immunoglobulin in Patients with Primary Immune Deficiencies

Intravenous immunoglobulin

The overall consensus among clinical immunologists is that a dose of intravenous immunoglobulin (IVIG) of 400-600 mg/kg/mo or a dose that maintains trough serum immunoglobulin (Ig) G levels greater than 500 mg/dL is desirable. Patients with meningoencephalitis require much higher doses (1 g/kg) and perhaps intrathecal therapy. Measurement of preinfusion (trough) serum IgG levels every 3 months until a steady state is achieved and then every 6 months if the patient is stable may be helpful in adjusting the dose of IVIG to achieve adequate serum levels. For persons who have a high catabolism of infused IgG, more frequent infusions (eg, every 2-3 wk) of smaller doses may maintain the serum level in the reference range. The rate of elimination of IgG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages or shorter intervals may be required.

For replacement therapy for patients with primary immune deficiency, all brands of IVIG are probably equivalent, although differences in viral inactivation processes (eg, solvent detergent vs pasteurization and liquid vs lyophilized) are observed. The choice of brands may depend on the hospital or home care formulary and the local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion in order to review for adverse events or other consequences.

Recording all side effects that occur during the infusion is crucial. Periodically monitoring liver and renal function test results, approximately 3-4 times a year, is also recommended. The US Food and Drug Administration (FDA) recommends that, for patients at risk for renal failure (eg, those with preexisting renal insufficiency, diabetes, volume depletion, sepsis, paraproteinemia, those >65 years, and those who use nephrotoxic drugs), recommended doses should not be exceeded and infusion rates and concentrations should be the minimum levels that are practicable.

The initial treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions in the initial treatment is high, especially in patients with infections and in those who form immune complexes. In patients with active infection, infusion rates may need to be slower and the dose halved (ie, 200-300 mg/kg), with the remaining dose given the next day to achieve a full dose. Treatment should not be discontinued. After achieving normal serum IgG levels, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIG products, adverse effects are much reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. 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.

Anticomplementary activity of IgG aggregates in the IVIG and the formation of immune complexes are thought to be related to the adverse reactions. The formation of oligomeric or polymeric IgG complexes that interact with Fc receptors and trigger the release of inflammatory mediators is another cause.

Most adverse reactions are rate related. Slowing the infusion rate or discontinuing therapy until symptoms subside may diminish the reaction. Pretreatment with ibuprofen (5-10 mg/kg every 6-8 h), 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. In some patients with a history of severe side effects, analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products using sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis are suggestive of osmotic injury to the proximal renal tubules. The infusion rate for sucrose-containing IVIG should not exceed 3 mg sucrose/kg/min. Risk factors for this adverse reaction include preexisting renal insufficiency, diabetes mellitus, dehydration, age older than 65 years, sepsis, paraproteinemia, and concomitant use of nephrotoxic agents.

For patients at increased risk, monitoring BUN and creatinine levels before starting treatment and prior to each infusion is necessary. If renal function deteriorates, the product should be discontinued. IgE antibodies to IgA have been reported to cause severe transfusion reactions in patients with IgA deficiency. A few reports of true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency (CVID) who developed IgE antibodies to IgA after treatment with immunoglobulin. However, in actual experience, this is very rare. In addition, this is not a problem for patients with X-linked agammaglobulinemia (Bruton disease) or severe combined immunodeficiency (SCID). Caution should be exercised in those patients with IgA deficiency (< 7 mg/dL) who need IVIG because of IgG subclass deficiencies. IVIG preparations with very low concentrations of contaminating IgA are advised (see the table below).

Other rare, serious adverse events include aseptic meningitis, thromboembolic events, immune hemolysis, and transfusion-related acute lung injury. These events are related to hyperosmolality or activated coagulation factor, or high sodium content, or presence of anti-D antibody.

Potential for transmission of pathogens cannot be completely ruled out. In order to reduce potential contamination of pathogens, all plasma for manufacture is tested at various levels and retested by viral marker and nucleic acid technology (NAT). Viral inactivation is achieved by dry heat, pasteurization, or irradiation solvent-detergent treatment, low pH exposure, or caprolate treatment. Viral removal is necessary to reduce the risk of transmission of nonenveloped viruses and includes precipitation, chromatography, and filtration including nanofiltration. Because of the introduction of various viral inactivation and removal processes, relatively large viruses, such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), are readily inactivated and can be effectively removed.

The main concern is prions that transmit spongiform encephalopathy (referred to as variant Creutzfeldt-Jacob disease [vCJD]). Currently, no blood tests or inactivation methods are applicable to prions. Fortunately, prions have not been detected directly in human blood and the potential for efficient removal of prions by the current manufacturing processes have been documented.

Subcutaneous immunoglobulin infusion

Subcutaneous infusion of Ig (SCIG) is an alternative method for patients with difficult venous access or for those who experience serious side effects from IVIG. Vivaglobin (ZLB Behring) is the first product to be approved in United States for SCIG therapy for the prevention of serious infection in patients with primary immune deficiency diseases (PIDD).

Vivaglobin is given on a weekly basis using an infusion pump, allowing patients to self-administer the injection at home. Recommended weekly dose of Vivaglobin is 100-200 mg/kg administered subcutaneously. Dose may be adjusted over time to achieve the desired clinical response and serum IgG levels. Initial dose can be calculated by multiplying the previous IVIG dose by 1.37, then dividing this dose into weekly doses based on the patient's previous IVIG treatment interval; for example, if IVIG was administered every 3 weeks, divide by 3. This dose of Vivaglobin provides a systemic IgG exposure comparable to that of the previous IVIG treatment.

Weekly administration of this dose leads to stable steady-state serum IgG levels with lower IgG peak levels and higher IgG trough levels compared with monthly IVIG treatment. The SCIG is well accepted by patients, mostly administered at home, and the risk of infusion reactions is even less than for IV infusions. SCIG was well tolerated in patients who had a history of severe reactions to IVIG infusions with the same product.

In clinical trials, the most frequent adverse event was injection-site reaction, consisting of mild or moderate swelling, redness, and itching. No serious local site reactions were observed, and reactions tended to decrease substantially after repeated use. Other adverse events irrespective of causality included headache, gastrointestinal disorder, fever, nausea, sore throat, and rash. As with all Ig products, patients receiving Ig therapy for the first time, receiving a new product, or not having received Ig therapy within the preceding 8 weeks may be at risk for developing reactions including fever, chills, nausea, and vomiting.

As with all immune globulin products, Vivaglobin is contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin preparations and in persons with selective immunoglobulin A deficiency who have known antibody against IgA. Vivaglobin is derived from human plasma. As with all plasma-derived products, the risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.

Table 2. Immune Globulin, Intravenous (Open Table in a new window)

Contents of table are adapted from the Manufacturers' literature.

Class Summary

Provides alternative method of administration for select patients.

Immune globulin, subcutaneous (Vivaglobin)

IgG antibodies that neutralize a wide variety of bacterial and viral agents. Neutralizes circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including INF-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells and augments suppressor T cells; blocks complement cascade. Peak serum IgG levels are lower and trough IgG levels are higher than those achieved with IVIG. SC administration results in stable steady-state IgG levels when administered weekly. Available as a 160-mg/mL SC injectable.