X-linked Immunodeficiency With Hyper IgM Medication

The mainstay of therapy for X-linked immunodeficiency with hyperimmunoglobulin M (XHIGM) is intravenous immunoglobulin (IVIG).

The overall consensus among clinical immunologists is that an IVIG dose of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels of more 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 IVIG dose to achieve adequate serum levels.

All brands of IVIG are probably equivalent, although viral inactivation processes differ (eg, solvent detergent vs pasteurization and liquid vs lyophilized). 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. 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, in patients at risk for renal failure, doses should not be exceeded and infusion rates and concentrations should be the minimum practicable levels.

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. 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 include dyspnea, nausea, vomiting, circulatory collapse, and loss of consciousness. Patients with more profound immunodeficiency or patients with active infections have more severe reactions.

Activation of complements by 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 related to infusion rate. 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 that use sucrose as a stabilizer may be associated with a greater risk for this renal complication. Acute tubular necrosis, vacuolar degeneration, and osmotic nephrosis suggest 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. In 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 describe true anaphylaxis in patients with IgA-deficiency (< 7 mg/dL) who have autoantibodies to IgA. IVIG preparations with very low concentrations of contaminating IgA are advised.

Other rare, serious adverse events include aseptic meningitis, thromboembolic events, immune hemolysis, and transfusion-related acute lung injury. These events are related to hyperosmolality, activated coagulation factor, 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 manufactured plasma is tested at various levels and retested with viral marker and nucleic acid technology (NAT). Viral inactivation is achieved using dry heat or pasteurization or irradiation solvent-detergent treatment, low pH exposure, or capreolate treatment. Viral removal is necessary to reduce the risk of nonenveloped virus transmission and includes precipitation, chromatography, and nanofiltration.

Because of the introduction of various viral inactivation and removal processes, relatively large viruses, such as HIV, and hepatitis B and C, 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]). No blood tests or inactivation methods are currently applicable to prions. Fortunately, prions have not been directly detected in human blood, and the potential for efficient removal of prions with the current manufacturing processes have been documented.

Table 2. Immune Globulin, Intravenous^{[9, 10, 11, 12]} (Open Table in a new window)

Table 3. Subcutaneous Immune Globulin (Open Table in a new window)

Class Summary

These agents are used for replacement of functional antibodies in IgG isotype.

Immune globulin IV (IGIV)

Neutralize circulating myelin antibodies through antiidiotypic 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; promotes remyelination; may increase CSF IgG levels (10%).

Class Summary

These agents are used for treatment of cryptosporidiosis.

Nitazoxanide (Alinia)

Inhibits growth of Cryptosporidium parvum sporozoites and oocysts and G lamblia trophozoites. Elicits antiprotozoal activity by interfering with pyruvate-ferredoxin oxidoreductase (PFOR) enzyme–dependent electron transfer reaction, which is essential to anaerobic energy metabolism. Available as a 20-mg/mL oral susp or 500-mg tab.

Class Summary

These agents are used for prophylaxis of PCP.

Trimethoprim and sulfamethoxazole (Septra, Bactrim)

Trimethoprim-sulfamethoxazole (TMP-SMX) is a fixed combination (1:5) of the 2 drugs and is usually bacteriostatic. The dosage ratios are set to produce a 20:1 ratio of SMX to TMP in blood and tissues, which gives maximal antibacterial activity. Both drugs block the folic acid metabolism cycle of bacteria and are much more active together than either agent alone. Sulfonamides are competitive inhibitors of the incorporation of p-aminobenzoic acid. TMP prevents reduction of dihydrofolate to tetrahydrofolate.

Class Summary

These agents are used for treatment of neutropenia.

Filgrastim (Neupogen)

Recombinant human granulocyte colony-stimulating factor G-CSF. Regulates the production of neutrophils within the bone marrow and affects neutrophil progenitor proliferation, differentiation, and selected end-cell functional activation (including enhanced phagocytic ability), priming of the cellular metabolism associated with respiratory burst, antibody-dependent killing, and the increased expression of some functions associated with cell-surface antigens. G-CSF is not species specific and has been shown to have minimal direct in vivo or in vitro effects on the production of hematopoietic cell types other than the neutrophil lineage. Daily administration has been shown to be safe and effective in causing a sustained increase in the neutrophil count and a decrease in infectious morbidity in children and adults with severe chronic neutropenia. Long-term daily administration is required to maintain clinical benefit. Absolute neutrophil count should not be used as the sole indication of efficacy. The dose should be individually adjusted based on the patient's clinical course as well as ANC.

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.