B-Cell and T-Cell Combined Disorders Medication

Unlike in other combined immunodeficiency syndromes, gamma-globulin replacement therapy does not appear to be beneficial in patients with ataxia-telangiectasia (AT) because of marked variation of humoral immunodeficiency with concomitant variable susceptibility to infections; however, individual patients may benefit. A study by Claret Teruel et al indicated that 7 out of 12 patients with AT received gamma-globulin due to immunoglobulin G (IgG) deficiency. Similarly, Kalfa et al described 9 patients with chronic mucocutaneous candidiasis (CMC) with selective antibody deficiency.^[13] All 9 had IgG2 deficiency with IgG4 deficiency in 8 patients and immunoglobulin A (IgA) deficiency in 3 patients. All 9 had recurrent severe lung infections and may have benefited from intravenous immunoglobulin (IVIG) therapy.

Replacement therapy using IVIG in patients with primary immunodeficiencies

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 at greater than 500 mg/dL is desirable. Patients (X-linked agammaglobulinemia) with meningoencephalitis require much higher doses (1 g/kg) and, perhaps, intrathecal therapy. Measurements 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, q2-3wk) 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 in patients with primary immunodeficiency, all brands of IVIG are probably equivalent, although differences in the viral inactivation processes (eg, solvent-detergent treatment versus pasteurization, liquid versus lyophilized powder) may be noted. The choice of brands may depend on the hospital or home care formulary and local availability and cost. The dose, manufacturer, and lot number should be recorded for each infusion 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 yearly, also is recommended. The Food and Drug Administration (FDA) recommends that for patients at risk for renal failure (eg, patients with preexisting renal insufficiency, diabetes, volume depletion, sepsis, or paraproteinemia; patients aged >65 y; and patients who use nephrotoxic drugs), recommended doses should not be exceeded and infusion rates and concentrations should be the minimum levels that are practicable.

Initial treatment should be administered under close supervision by experienced personnel. The risk of adverse reactions during initial treatments is high, especially in patients with infections and patients 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 administered the next day to achieve a full dose. Treatment should not be discontinued. After achieving reference range 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 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 infusion may prevent adverse reactions. In some patients with a history of severe adverse 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 acute renal failure. 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 and creatinine levels before starting treatment and prior to each infusion is necessary. If renal function deteriorates, discontinue the product.

IgE antibodies to IgA have been reported to cause severe transfusion reactions in patients with IgA deficiency. A few reports exist of true anaphylaxis in patients with selective IgA deficiency and common variable immunodeficiency who developed IgE antibodies to IgA after IVIG treatment. However, in actual experience, this reaction is very rare. In addition, anaphylaxis is not a problem in patients with X-linked agammaglobulinemia (Bruton disease) or severe combined immunodeficiency (SCID). Exercise caution in 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.

Table. Intravenous Immunoglobulin Therapy^{[21, 30, 31, 32]} (Open Table in a new window)

Although IVIG may improve the ability of some patients to handle infections, aggressive treatment of acute bacterial infections with specific antibiotics remains necessary. In patients with clinically significant T-cell deficiency, prophylaxis may be warranted against Pneumocystis carinii pneumonia, either in the form of oral trimethoprim-sulfamethoxazole (Bactrim or Septra) or pentamidine.

IVIG replacement therapy has not been effective in treating patients with AT and CMC. However, a trial of IVIG may be warranted in other patients with combined B-cell and T-cell deficiency who lack antibody production to specific antigens (eg, tetanus, diphtheria, or polysaccharide antigens to pathogens such as Haemophilus influenzae or Streptococcus pneumoniae).

Several reports describe subcutaneous infusion in children in whom IV access is difficult. Stiehm et al administered dosages of 100 mg/kg/wk (ie, 1 mL/kg of a 10% IV solution) or 250 mg/kg (ie, 2.5 mL/kg) every 3 weeks.^[14] Recently, the FDA approved a form of immunoglobulin for subcutaneous use. Exercise caution when treating patients with absent IgA serum levels because of the possibility of anaphylaxis. Some researchers urge screening these patients for serum anti-IgA antibody levels; others use Gammagard.

In patients younger than 2 years, use of passive immunization against respiratory syncytial virus (RSV) should be considered. Severe RSV bronchiolitis and pneumonitis may contribute to the development of chronic lung disease.

Class Summary

Prevention of RSV in immunodeficient patients is possible with passive immunization with RSV-specific polyclonal IVIG or humanized mouse monoclonal IgG.

RSV-IVIG (RespiGam)

Polyclonal human immunoglobulin made by selecting donors with high titers of anti-RSV antibody. With monthly infusion, protects high-risk infants against severe RSV disease. In clinical trials, RSV-IVIG reduced hospitalization for non-RSV infections lower respiratory tract and rates of otitis media compared with placebo.

Palivizumab (Synagis)

Humanized mouse monoclonal IgG preparation specifically directed toward RSV.

Class Summary

In patients with clinically significant T-cell deficiency, prophylaxis against P carinii pneumonia may be warranted. Prophylaxis may be in the form of oral trimethoprim-sulfamethoxazole (Bactrim or Septra) or pentamidine.

In patients with CMC, topical antifungal therapies are usually not effective. Oral candidiasis can be treated with clotrimazole troches instead of oral nystatin solution. Systemic oral antifungal drugs are occasionally effective and can improve the quality of life for affected patients. However, relapse after cessation of the antifungal therapy is common. Reports described successful treatment with cimetidine and zinc sulphate in patients with CMC.

Trimethoprim-sulfamethoxazole (Bactrim, Septra, Cotrim)

Inhibits bacterial growth by inhibiting synthesis of dihydrofolic acid.

Administration on Mondays, Wednesdays, and Fridays instead of 3 consecutive days also effective. This regimen may be especially necessary if physician must desensitize patient because of drug allergy; spreading dose throughout the week allows for continued attachment of drug to IgE on mast cells without degranulation.

Pentamidine (Pentam-300, Pentacarinat, NebuPent)

Antiprotozoal agent used for prophylaxis and treatment of P carinii infection. Inhibits growth of protozoa by blocking oxidative phosphorylation and inhibiting incorporation of nucleic acids into RNA and DNA, inhibiting protein and phospholipid synthesis.