eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology
Agammaglobulinemia: Treatment & Medication
Updated: Nov 11, 2008
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
- Multimedia
Treatment
Medical Care
Because a patient with agammaglobulinemia is unable to produce specific antibodies, the primary medical treatment is to replace immunoglobulin (Ig). Aggressive treatment with antibiotics for bacterial infections may prevent long-term complications. Live viral vaccines (eg, measles, mumps, rubella [MMR]) are contraindicated in these patients and their families because they may cause vaccine-related infections.
- Intravenous Ig (IVIG) results in improved clinical status with a decrease in serious infections, such as pneumonia, meningitis, and GI infection. This also appears to be the case for hypogammaglobulinemia secondary to malignancy.
- Patients who received high-dose IVIG (400-500 mg/kg every 3-4 wk) and who maintained IgG levels higher than 500 mg/dL had fewer hospitalizations and infections. Although the goal is to maintain a trough serum IgG level of at least 500 mg/dL, in practice, patients are treated so that they have fewer infections. This may involve higher doses, more frequent infusions, or both. Patients with bronchiectasis need higher doses (eg, 600 mg/kg). Because of the blood-brain barrier, patients with viral meningitis require 1000 mg/kg.
- Intravenous access may be difficult to obtain in some patients. Although intramuscular injection of IgG immune serum globulin (ISG) can be performed (0.75 mL/kg), much lower levels result; thus, injections should be given more frequently. Subcutaneous IgG (SCIG) administration is now available with a different preparation.33 Administration every 14 days of 200 mg/kg body weight resulted in serum IgG levels greater then 7 g/L and was tolerated well in adult patients with X-linked agammaglobulinemia (XLA) and common variable immunodeficiency (CVID).34,35 Its advantage is that SCIG can be administered in a patient's home without a visiting nurse. The disadvantages are the lack of medical supervision at home and questions of compliance. These considerations need to be addressed on an individual patient basis.
- In patients with chronic upper or lower respiratory tract infections and subsequent structural changes, strategic long-term broad-spectrum antibiotics may be needed, in addition to chest physiotherapy and sinus surgery.
- An intriguing report from Brazil showed clinical improvement in patients with XLA without IVIG replacement therapy but receiving aggressive respiratory physiotherapy.9
- Specific antibiotic choices must cover the usual polysaccharide-encapsulated organisms. Higher doses and longer courses are commonly required.
- Some patients develop chronic sinusitis despite regular IVIG replacement therapy every 3 weeks. These patients are challenging to treat because antibiotics, N -acetylcysteine, and topical intranasal corticosteroid therapies fail to clear pathogens and do not decrease sinus inflammation.
Surgical Care
Because of the possible development of chronic sinusitis, endoscopic procedures with irrigation may be invaluable in obtaining cultures for microbiological studies. In addition, further surgical intervention may be required to promote sinus drainage. Similarly, obtaining other samples for culture, such as lymph node samples in patients presenting with adenopathy or bronchoalveolar lavage fluid samples in patients with pneumonia who are unable to provide sputum specimen, will allow for a greater selection of appropriate antibiotics for treatment.
Consultations
Because of the frequent infections and subsequent administrations of antibiotics, treatment requires close partnership with pediatric infectious-disease experts. Autoimmune disorders are treated similarly to diseases in patients with intact humoral immunity; patients may require the expertise of a pediatric rheumatologist. Despite aggressive antibiotic therapy, surgical intervention may be required for chronic sinusitis or for chronic lung disease with abscess, pleural effusion, or other conditions. Concomitant consultation with a pediatric pulmonologist and/or otolaryngologist may be needed.
Medication
Replacement therapy with intravenous immunoglobulin in patients with primary immune deficiencies
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 IgG levels greater than 500 mg/dL is desirable. Patients with X-linked agammaglobulinemia (XLA) 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. 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 immunoglobulin (Ig)G 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 are observed (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 yearly, 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 y; 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 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 are 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 the 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 IgA-deficient patients. True anaphylaxis has been reported in patients with selective IgA deficiency and common variable immunodeficiency (CVID) who developed IgE antibodies to IgA after treatment with Ig. In actual experience, however, this is very rare. In addition, this is not a problem for patients with XLA (Bruton disease) or severe combined immunodeficiency (SCID). Caution should be exercised in patients who are IgA deficient (<7 mg/dL) and need IVIG because of IgG subclass deficiencies. IVIG preparations with very low concentrations of contaminating IgA are advised.
Immune Globulin, Intravenous
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Table
| Brand(Manufacturer) | Manufacturing Process | pH | Additives* | 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 | 0.25M 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 |
| 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) | 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, sucrose-free, and maltose-free | Ready-to-use solution 10% | <25 |
| Brand(Manufacturer) | Manufacturing Process | pH | Additives* | 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 | 0.25M 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 |
| 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) | 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, sucrose-free, and maltose-free | Ready-to-use solution 10% | <25 |
*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).
Contents of table are adapted from the following sources:
- Manufacturers' literature.
- Siegel J. The Product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005; 25(11 Pt 2):78S-84S.
- Shah S. Pharmacy consideration for the use of IGIV therapy. Am J Health-Syst Pharm. 2005; 62(Suppl 3):S5-11.
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.
Antibodies
Prevention of respiratory syncytial virus (RSV) in immunodeficient patients is possible with passive immunization with RSV-specific polyclonal IVIG or humanized mouse monoclonal IgG.
RSV-IVIG (RespiGam)
Polyclonal human IVIG, which has been preselected for high-titer RSV antibody levels may be effective for other viral respiratory infections also.
Adult
Pediatric
750 mg/kg IV qmo
Increases toxicity of live virus vaccine; do not administer within 9 mo of vaccine
Documented hypersensitivity; cyanotic congenital heart disease
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adverse effects may include fever, headaches, and nausea; see precautions with other IVIG preparations.
Palivizumab (Synagis)
A humanized mouse monoclonal IgG preparation specifically directed toward RSV.
Adult
Pediatric
15 mg/kg IM qmo
None reported
Documented hypersensitivity; cyanotic congential cardiac disease
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in thrombocytopenia or other coagulation disorders
Immune globulin, subcutaneous
Subcutaneous administration of immune globulin provides an alternative method of administration to intravenous in 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.
Adult
Note: Do not exceed 15 mL (3200 mg) SC per injection site; administration rate not to exceed 20 mL/h per injection site
Previously on IVIG: Weekly SC dose (g/wk) = (previous IVIG dose X 1.37) divided by previous administration interval in wk; initiate 1 wk after last IVIG dose
Recommended weekly dose: 100-200 mg/kg/wk SC
Pediatric
<2 years: Not established
>2 years: Administer as in adults
Globulin preparation may interfere with immune response to live-virus vaccine (MMR) and reduce efficacy (do not administer within 3 mo of vaccination)
Documented hypersensitivity; IV administration; selective IgA deficiency (serum IgA level <0.05 g/L) with known antibody against IgA
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include swelling, redness, and itching at injection site; for SC administration only; preferred SC administration sites include abdomen, thighs, upper arms, or lateral hip; initiate 1 wk after regularly scheduled IVIG infusion; does not contain preservative (discard unused portion); may cause fever, chills, nausea, or vomiting when switching from one immune globulin product to another or if > 8 wk since last administered; do not shake product
More on Agammaglobulinemia |
| Overview: Agammaglobulinemia |
| Differential Diagnoses & Workup: Agammaglobulinemia |
 Treatment & Medication: Agammaglobulinemia |
| Follow-up: Agammaglobulinemia |
| Multimedia: Agammaglobulinemia |
| References |
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Further Reading
Keywords
agammaglobulinemia, hypogammaglobulinemia, X-linked agammaglobulinemia, XLA, X-linked hypogammaglobulinemia, early-onset agammaglobulinemia, late-onset agammaglobulinemia, B-cell development, B-cell maturation, Bruton tyrosine kinase, Btk, Bruton agammaglobulinemia, immunodeficiency, Ig levels, B-cell linker protein, BLNK, common variable immunodeficiency, CVID, hyper-IgM syndrome, intrauterine growth retardation, X-linked immunodeficiency with hyper IgM
transient hypogammaglobulinemia of infancy, B-cell disorders, spondyloepiphyseal dysplasia, retinal dystrophy, growth hormone deficiency, pneumonia, bacteremia, sinusitis, bronchiectasis, Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, gastroenteritis, bronchiolitis, arthritis, osteomyelitis, poliovirus, echovirus, coxsackievirus, encephalomyelitis, meningoencephalitis, LACH syndrome, colitis, WHIM syndrome, Good syndrome, human immunodeficiency virus infection, HIV, Duncan disease, Purtilo syndrome, Epstein-Barr virus, mononucleosis
