What is the role of IVIg replacement therapy in the treatment of severe combined immunodeficiency (SCID)?

Updated: Apr 28, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD  more...
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Answer

The consensus among clinical immunologists is that an IVIg dose of 400-600 mg/kg each month or a dose that maintains trough serum immunoglobulin (Ig) G levels above 500 mg/dL is desirable. Patients with X-linked agammaglobulinemia and 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 weeks) 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.

Numerous IVIg preparations are available. [38, 39, 40, 41] For replacement therapy in patients with primary immune deficiency, all brands of IVIg are probably equivalent, though viral inactivation processes differ (eg, solvent detergent vs pasteurization and ready-to-use liquid vs lyophilized powder requiring reconstitution). Additional knowledge of IgA content of a particular brand may be necessary depending on the particular patient. The choice of brands may be dependent on the hospital or home care formulary and the local availability and cost. The Immune Deficiency Foundation provides a useful resource that describes the characteristics of immunoglobulin products.

Monitoring liver and renal function test results periodically (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 older than 65 years) and those who use nephrotoxic drugs, the recommended doses should not be exceeded and the infusion rates and concentrations should be at the minimum practicable levels.

Initial IVIg treatment should be administered under the close supervision of experienced personnel. The risk of adverse reactions at this point is high, especially in patients with infections and those who form immune complexes. In patients with active infection, infusion rates may have to be reduced and the dose halved (ie, 200-300 mg/kg), with the remainder of the dose given the next day. Treatment should not be discontinued. Once normal serum IgG levels are reached, adverse reactions are uncommon unless patients have active infections.

With the new generation of IVIg products, adverse effects are greatly reduced. Adverse effects include tachycardia, chest tightness, back pain, arthralgia, myalgia, hypertension or hypotension, headache, pruritus, rash, and low-grade fever. More serious reactions are dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with 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 orally every 6-8 hours), acetaminophen (15 mg/kg/dose orally), diphenhydramine (1 mg/kg/dose orally), or hydrocortisone (6 mg/kg/dose, not to exceed 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 of this 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 blood urea nitrogen (BUN) and creatinine levels before starting the treatment and before 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 IgA-deficient patients. A few reports exist of true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency who developed IgE antibodies to IgA after treatment with immunoglobulin. In actual experience, however, this is very rare. In addition, this is not a problem for patients with X-linked agammaglobulinemia (Bruton disease) or severe combined immunodeficiency.

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.


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