Pediatric Bruton Agammaglobulinemia Medication

Updated: Mar 18, 2019
  • Author: Terry W Chin, MD, PhD; Chief Editor: Harumi Jyonouchi, MD  more...
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Medication

Medication Summary

The overall consensus among clinical immunologists regarding replacement therapy with IVIG in patients with primary immune deficiencies is that an IVIG dose of 400-600 mg/kg/mo or a dose that maintains trough serum IgG levels greater than 500 mg/dL is desirable. The number and severity of infectious complications is inversely correlated with the dose of IVIG administered. A recent consensus statement suggests that maintaining trough IgG levels greater than 800 mg/dL prevents serious bacterial illness and enteroviral meningoencephalitis. [55] However, if infections continue to be a problem, increasing the trough level up to 1000 mg/dL is an option. [56]

Measure 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. It 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 IVIG may be higher during a period of active infection; measuring serum IgG levels and adjusting to higher dosages or shorter intervals may be required.

SCIG administration is also possible. [57] The recommended dose is 100-200 mg/kg SC every week. The initial weekly SC dose can be calculated by multiplying the previous IVIG dose by 1.37 and then dividing that dose into weekly doses, based on the patient's previous IVIG treatment interval. For example, if IVIG dosage is 200 mg/kg every 3 weeks, multiply 200 mg/kg by 1.37 and then divide by 3 to get a calculated dose of 91 mg/kg SC every week. The calculated SCIG dose provides systemic exposure similar to that of the previous IVIG dose. SCIG dose should be initiated 1 week after the last IVIG dose. For SCIG administration, do not exceed 15 mL (3200 mg) per injection site, and the administration rate is not to exceed 20 mL/h per injection site. In a review of seven studies on SCIG, the incidence of infection was found to be inversely related to the trough serum IgG level. [58] Therefore, maintaining higher IgG levels may be beneficial but no given level was found to be adequate for all patients.

Recently, a cost comparison analysis was made in France between SCIG and IVIG. [59] It appeared that SCIG appeared to be 25% less expensive.

Preinfusion (trough) serum IgG levels are measured every 3 months until a steady state is achieved and then every 6 months if the patient is stable. These measurements may be helpful in adjusting the dose of IVIG or SCIG to achieve adequate serum levels. For persons in whom the catabolism of infused IgG is high, more frequent (eg, every 2-3 wk) IV infusions of smaller doses may maintain the serum level within the reference range. The rate of elimination of IgG may be higher during a period of active infection. Therefore, serum IgG levels may need to be measured more frequently, doses may need to be increased, or shorter intervals may be required.

For replacement therapy in patients with primary immune deficiency, all brands of IVIG are probably equivalent, although viral inactivation processes (eg, solvent detergent vs pasteurization and liquid vs lyophilized) differ. The choice of brand may depend on the hospital or home care formulary and on local availability and cost. In addition, whether home SCIG administration is appropriate must be determined. In patients who have IV access problems or who develop adverse effects with IVIG administration (eg, headache, myalgias), SCIG is an alternative. Questions regarding compliance need to be answered. The requirement of weekly infusions and local reactions at the site of infusions are disadvantages.

In addition, contraindications include patients with thrombocytopenia or other bleeding disorders and patients who are receiving anticoagulant therapy. SCIG was shown to be equal in efficacy to the same dose administered IV. The dose, manufacturer, and lot number should be recorded for each infusion to facilitate review for adverse events or other consequences. Recording of all adverse effects that occur during the infusion is crucial.

Periodic liver and renal function testing, approximately 3-4 times yearly, is also recommended. The US Food and Drug Administration (FDA) advises that, in patients at risk for renal failure, the recommended doses should not be exceeded and that infusion rates and concentrations should be at the practicable minimum levels. Examples of patients at risk for renal failure include patients older than 65 years; patients who use nephrotoxic drugs; and patients with preexisting renal insufficiency, diabetes mellitus, volume depletion, sepsis, or paraproteinemia.

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

With the new generation of IVIG products, adverse effects are 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 and patients with active infections have more severe reactions.

The activation of complement due to 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 crystallizable fragment (Fc) receptors and that trigger the release of inflammatory mediators is a 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; not to exceed 1000 mg/dose or 2.6 g/24 h if age < 12 y), diphenhydramine (1 mg/kg/dose; not to exceed 50 mg/dose), and/or hydrocortisone (6 mg/kg/dose; not to exceed 100 mg/dose) 1 hour before the infusion may prevent adverse reactions. In some patients with a history of severe adverse effects, therapy with analgesics and antihistamines may be repeated.

Acute renal failure is a rare but significant complication of IVIG treatment. Reports suggest that IVIG products with 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/kg/min based on the amount of sucrose. 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 the BUN and creatinine levels before starting the treatment and prior to each infusion is necessary. If the patient's renal function deteriorates, the treatment should be discontinued.

IgE antibodies to IgA have rarely been reported to cause severe transfusion reactions in patients with IgA deficiency. A few cases of true anaphylaxis have been reported in patients with selective IgA deficiency and CVID who developed IgE antibodies to IgA after treatment with Ig. However, this is rare in actual experience. In addition, this is not a problem in patients with XLA or in patients with SCID. Caution should be exercised in patients with IgA deficiency (< 7 mg/dL) who need IVIG. (IgA levels can be low in patients with selective IgA deficiency, in patients with CVID, and in some patients with IgG-subclass deficiencies.) IVIG preparations with low concentrations of contaminating IgA are advised in these situations (see the Table below).

Although IVIG has improved the patient's ability to handle infections, aggressive treatment for acute bacterial infections with specific antibiotics continues to be necessary. No difference in efficacy among the brands of IVIG is recognized. One review indicated that IVIG at a mean dose of 0.42 g/kg in 162 treatment years resulted in an infection rate similar to the general pediatric population. All 18 children in that study had normal growth patterns. Thus far, the possibility of other infectious agents, notably hepatitis C virus (HCV), has not been a problem in the newer preparations of IVIG, with the additional viral inactivations steps incorporated into the manufacturing processes.

Table 1. Immune Globulin, Intravenous (Open Table in a new window)

Brand(Manufacturer)

Manufacturing Process

pH

Additives (IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors [eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs].)

Parenteral Form and Final Concentrations

IgA Content mcg/mL

Carimune NF

(ZLB Behring)

Kistler-Nitschmann fractionation, pH 4 incubation, nanofiltration

6.4-6.8

6% solution: 10% sucrose, < 20 mg NaCl/g protein

Lyophilized powder 3, 6, 9, 12%

Trace

Flebogamma

(Grifols USA)

Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization

5.1-6

Sucrose free, contains 5% D-sorbitol

Liquid 5%

< 50

Gammagard Liquid 10%

(Baxter Bioscience)

Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation

4.6-5.1

0.25 M glycine

Ready-for-use liquid 10%

37

Gammar-P IV

(ZLB Behring)

Cohn-Oncley fraction II/III, ultrafiltration, pasteurization

6.4-7.2

5% solution: 5% sucrose, 3% albumin, 0.5% NaCl

Lyophilized powder 5%

< 20

Gamunex

(Talecris Biotherapeutics)

Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation

4-4.5

Contains no sugar, contains glycine

Liquid 10%

46

Gammaplex

(Bio Products)

Solvent/detergent treatment targeted to enveloped viruses; virus filtration using Pall Ultipor to remove small viruses including nonenveloped viruses; low pH incubation

4.8-5.1

Contains sorbitol (40 mg/mL); do not administer if fructose intolerant

Ready-for-use solution 5%

< 10

Iveegam EN

(Baxter Bioscience)

Cohn-Oncley fraction II/III, ultrafiltration, pasteurization

6.4-7.2

5% solution: 5% glucose, 0.3% NaCl

Lyophilized powder 5%

< 10

Polygam S/D

Gammagard S/D

(Baxter Bioscience for the American Red Cross)

Cohn-Oncley cold ethanol fractionation followed by ultracentrafiltration and ion exchange chromatography, solvent detergent treated

6.4-7.2

5% solution: 0.3% albumin, 2.25% glycine, 2% glucose

Lyophilized powder 5%, 10%

< 1.6 (5% solution)

Octagam

(Octapharma USA)

9/24/10: Withdrawn from market because of unexplained reports of thromboembolic events

Cohn-Oncley fraction II/III, ultrafiltration, low pH incubation, S/D treatment pasteurization

5.1-6

10% maltose

Liquid 5%

200

Panglobulin

(Swiss Red Cross for the American Red Cross)

Kistler-Nitschmann fractionation, pH 4 incubation, trace pepsin, nanofiltration

6.6

Per gram of IgG: 1.67 g sucrose,< 20 mg NaCl

Lyophilized powder 3, 6, 9, 12%

720

Privigen

(CSL Behring)

pH 4 incubation, octanoic acid fractionation, depth filtration, and virus filtration

4.6-5

10% solution; Preservative-free and sucrose- and maltose-free

Ready-to-use solution 10%

25

Contents of table are adapted from the following sources:

  1. Manufacturers' literature.

  2. Siegel J. The Product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005; 25(11 Pt 2):78S-84S.

  3. Shah S. Pharmacy consideration for the use of IGIV therapy. Am J Health-Syst Pharm. 2005; 62(Suppl 3):S5-11.

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

Brand(Manufacturer)

Manufacturing Process

pH

Additives

Parenteral Form and Final Concentrations

IgA Content mcg/mL

Vivaglobin

(ZLB Behring)

Cold ethanol fractionation, pasteurization

6.4-7.2

2.25% glycine, 0.3% NaCl

Liquid 16% (160 mg/mL)

< 50 mcg/mL

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Antibiotics

Class Summary

Antibiotics are most commonly used to treat sinopulmonary infections caused by polysaccharide-encapsulated bacteria (S pneumoniae, H influenzae type b).

Amoxicillin, amoxicillin/clavulanate, and cefuroxime axetil are the drugs of choice for the common extracellular bacteria that cause sinopulmonary infections. Ceftriaxone is used in patients with more severe sinopulmonary infections, in patients who respond poorly to oral antibiotics, and in patients with significant bronchiectasis. Ceftriaxone is also used for penicillin-resistant pneumococcal infections. Clarithromycin covers mycoplasmal infections and many bacterial sinopulmonary infections. Vancomycin is chosen in patients who are allergic to cephalosporins and when the isolate is resistant to penicillin. Fluoroquinolones are valuable for respiratory pathogens, including staphylococci, and in patients with multiple antibiotic allergies.

Amoxicillin (Trimox, Amoxil, Biomox)

Interferes with synthesis of cell wall mucopeptides during active multiplication, resulting in bactericidal activity against susceptible bacteria.

Amoxicillin/clavulanate (Augmentin)

Drug combination treats bacteria resistant to beta-lactam antibiotics. In children >3 mo, base dose on amoxicillin content. Because of different amoxicillin-clavulanic acid ratios in 250-mg tab (250:125) and in 250-mg chewable tab (250:62.5), do not use 250-mg tab until child weighs >40 kg

Cefuroxime axetil (Ceftin)

Second-generation cephalosporin that maintains gram-positive activity of first-generation cephalosporins; adds activity against Proteus mirabilis, H influenzae, Escherichia coli, Klebsiella pneumoniae, and M catarrhalis.

Ceftriaxone (Rocephin)

Third-generation cephalosporin with broad-spectrum activity; efficacy against resistant organisms. Arrests bacterial growth by binding to ≥ 1 penicillin-binding proteins.

Clarithromycin (Biaxin)

Inhibits bacterial growth, possibly by blocking dissociation of peptidyl tRNA from ribosomes, causing RNA-dependent protein synthesis to arrest.

Vancomycin (Lyphocin, Vancocin, Vancoled)

Potent antibiotic directed against gram-positive organisms and active against enterococcal species. Indicated for patients who cannot receive penicillins and cephalosporins, in patients in whom these failed, or in those with infections due to resistant staphylococci. To prevent toxicity, current recommendation is to assay vancomycin trough levels after third dose with sample drawn 0.5 h before next dose. Use CrCl to adjust dose in renal impairment.

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Bronchodilators

Class Summary

Inhaler bronchodilator therapy is the mainstay of pulmonary care in most patients with XLA. A combination of a beta2-agonist (eg, albuterol, salmeterol) with a high-potency steroid (eg, budesonide, fluticasone) is conventional care.

Inhalers are used to relieve bronchoconstriction and decrease the inflammatory response in the respiratory tree. Both pulmonary and nasal inhalers may be needed. Inhaler use is hampered in young children and in others who cannot understand the technique of administration and in older individuals who are unable to achieve forceful inhalation. Adding a spacer is customary to improve coordination in children. If patients cannot reliably use a metered-dose inhaler, a nebulizer may be an option. Steroid inhalation is followed by rinsing the mouth to prevent thrush.

Albuterol (Proventil, Ventolin)

Relaxes bronchial smooth muscle by action on beta2-receptors with little effect on cardiac muscle contractility. Is also available as a solution for nebulization. MDI delivers 90 mcg/actuation.

Salmeterol (Serevent Diskus)

Can relieve bronchospasms by relaxing the smooth muscles of the bronchioles. Effect may also facilitate expectoration. Each actuation delivers 50 mcg.

Formoterol (Foradil)

Can relieve bronchospasms by relaxing smooth muscles of bronchioles in conditions associated with bronchitis, emphysema, asthma, or bronchiectasis. Effect may also facilitate expectoration. Shown to improve symptoms and morning peak flows.

Incidence of side effects higher when administered at more frequent doses than recommended. Bronchodilating effect lasts >12 h. Use in addition to regular use of anticholinergic agents. Useful in cases in which bronchodilators are used frequently. Available as PO inhalant powder cap and administered via Aerolizer inhaler.

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Corticosteroids, Inhaled

Class Summary

These agents are used to prevent and decrease inflammatory reaction within airway.

Beclomethasone (Qvar)

Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, decreasing airway hyperresponsiveness. Some patients may require higher doses of inhaled beclomethasone. Qvar available as 40 mcg or 80 mcg per actuation.

Fluticasone (Flovent HFA, Flovent Diskus)

Has extremely potent vasoconstrictive and anti-inflammatory activity. Has weak HPA-axis inhibitory potency when applied topically. Some patients may require higher doses. Various inhalant devices deliver different dosages per actuation. Flovent HFA delivers 44 mcg, 110 mcg, and 220 mcg per actuation, whereas Flovent Diskus is specially designed with blister pack containing 50 mcg as a powder for inhalation.

Flunisolide (AeroBid, AeroSpan)

Has extremely potent vasoconstrictive and anti-inflammatory activity. Has weak HPA-axis inhibitory potency when applied topically. Some patients may require higher doses. AeroBid (flunisolide CFC) delivers about 250 mcg/actuation. AeroSpan (flunisolide HFA) delivers about 80 mcg/actuation.

Budesonide inhaled (Pulmicort Turbuhaler, Pulmicort Respules)

Inhibits bronchoconstriction mechanisms, produces direct smooth muscle relaxation, and may decrease number and activity of inflammatory cells, decreasing airway hyperresponsiveness. Available in various inhaled products. Pulmicort Turbuhaler delivers a powder that is inhaled (200 mcg/actuation). Pulmicort Flexhaler delivers a powder for inhalation as either 90 mcg or 180 mcg per dose. Pulmicort Respules is an inhalation susp administered via nebulization (available in 2 strengths: 0.25 mg/2 mL, 0.5 mg/2 mL).

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