Medical Care
Until gene therapy becomes developed, [48] the mainstay therapy for Bruton agammaglobulinemia, formally termed X-linked agammaglobulinemia (XLA), and other primary antibody deficiencies 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. On the other hand, it has been demonstrated that the dendritic and T-cell responses are normal toward influenza in patients with XLA after administration of inactivated trivalent influenza vaccine. [49]
IVIG administration has supplanted IMIG injections in most instances. [50] SCIG administration is also possible and offers the advantage of providing IgG levels that are relatively constant compared with the peaks and troughs observed with monthly intravenous therapy.
Numerous studies have shown that IVIG and SCIG given in equal doses provide equal infection prevention in patients with primary antibody deficiency syndromes. [51] A major advantage is that SCIG can be administered at home. However, subcutaneous administration causes frequent local discomfort in various sites in the abdomen, thighs, upper arms, and/or lateral hips. In addition, whether home health care is appropriate for each patient must be evaluated. Not only is compliance an issue, but the lack of close medical observation is also a concern because these patients no longer need to come to the hospital for monthly infusions.
IVIG results in improved clinical status with a decrease in serious infections, such as pneumonia, meningitis, and GI infection. IVIG doses are usually 400-600 mg/kg/mo or more. The administration interval is usually every 3-4 weeks, based on the average IgG half-life of 21-28 days. The dose and interval are chosen based on the clinical response. Maintaining a trough serum IgG level of approximately 500-800 mg/dL is necessary.
Clinical situations in which higher IVIG doses are given include, but are not limited to, chronic pulmonary infection and chronic enteroviral infection. Therefore, patients with bronchiectasis may need higher doses (eg, 600 mg/kg). Because of the blood-brain barrier, patients with viral meningitis may require 1000 mg/kg.
For SCIG administration, 14 days of 200 mg/kg body weight resulted in serum IgG levels of more than 7 g/L and was tolerated well in adult patients with XLA and CVID. [52, 53]
Antibiotics are frequently required to manage the infectious complications of antibody deficiencies. Obtain appropriate cultures to identify causative microorganisms and to establish sensitivities; these results allow for optimal antibiotic therapy. 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.
Because most infections are sinopulmonary and involve encapsulated bacterial agents, first-line oral antibiotics include amoxicillin, amoxicillin/clavulanate, and cefuroxime axetil. Intravenous ceftriaxone may be required for chronic pulmonary infection, acute severe pneumonia, or sepsis.
As with other patient populations, the risk for penicillin-resistance among S pneumoniae is an increasing concern; ceftriaxone, cefotaxime, and vancomycin are used to treat penicillin-resistant organisms.
Less frequent, but significant, infectious agents include Mycoplasma and Ureaplasma species; these organisms are best treated with clarithromycin, which is generally better tolerated than erythromycin in terms of adverse GI effects. Clarithromycin is more effective than azithromycin.
Antibiotic therapy for antibody deficiencies is in the high end of the dose range for immunocompetent individuals, and the duration is the same or longer. Some clinicians advocate rotating the use of antibiotics in select patients with bronchiectasis and frequent exacerbations.
Opportunistic organisms are uncommon in XLA, but the risk of infection is increased, particularly in the presence of chronic debilitating pulmonary disease or (more rarely) chronic colitis. Pneumocystis carinii and B cepacia can be etiologic agents in these settings. Trimethoprim-sulfamethoxazole is the first-line drug for both.
Recently released antibiotics such as linezolid for penicillin-resistant pneumococci are presumably effective, although results in primary immunodeficiency diseases are not yet published.
Many infections require interventions in addition to antibiotics. Recurrent or chronic pulmonary infections require annual PFTs. Children older than 5 years should be able to undergo these tests.
Bronchodilators, inhaled corticosteroids, and leukotriene modifiers are integral in the therapy of many patients. 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. [54]
Sinusitis is typically chronic in older patients and requires therapy with nasal steroids, saline sprays, and surgical intervention in some cases. 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.
Chronic eczema is treated with moisturizing creams and topical steroids, as in immunocompetent patients. Uncontrolled atopic dermatitis is associated with a greater risk for superinfection than that of topical steroid use.
Nutritional intervention or supplementation and the use of multivitamin and mineral preparations are usually unnecessary in XLA, although some patients with autoimmune colitis occasionally require such therapy. Determining the etiology of the diarrhea (often infectious) is more important.
Liver function tests are recommended annually because autoimmune hepatitis and hepatitis C may progress subclinically.
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.
Patients with chronic sinusitis who may benefit from surgical drainage procedures usually require a consultation with an otolaryngologist, as do children with recurrent otitis media who may improve with the placement of tympanostomy tubes.
Surgical interventions for pulmonary infections include diagnostic and therapeutic thoracentesis, lung biopsy, and care for lung abscesses and bronchopleural fistulas.
Consultations
A pulmonologist, allergist/immunologist, infectious disease specialist, gastroenterologist, rheumatologist and/or hematologist may be consulted to manage specific complications.
Pulmonologists are particularly valuable in evaluating radiological findings, assisting with bronchodilator therapy, and interpreting detailed PFT results. Bronchoscopy with washings for culture of both aerobic and anaerobic organisms, fungal, mycobacterial, and viral pathogens may be needed in cases of pneumonia or bronchitis.
Allergy/immunology specialists are trained in the diagnosis and management of primary immunodeficiency disorders and are particularly valuable in diagnosing XLA and guiding IVIG therapy.
Infectious disease specialists are often consulted to determine the infectious etiologies, and they can recommend first-line antibiotics.
Gastroenterologists are essential in the diagnosis and management of inflammatory bowel disease.
Hematologists and clinical immunologists must collaborate to treat autoimmune cytopenias because immunosuppressive therapies for these hematologic disorders further compromise immune function in patients with XLA.
Despite aggressive antibiotic therapy, surgical intervention may be required for chronic sinusitis or for chronic lung disease with abscess, pleural effusion, or other conditions.
Diet
Most children and adults with XLA should maintain a normal and nutritious diet.
Patients with inflammatory bowel disease may require a low-fat diet and vitamin supplementation.
Nutritional supplementation with products such as PediaSure, Ensure, or Vivonex is necessary for some patients with persistent malabsorption and malnutrition.
Activity
Encourage patients with XLA to exercise actively, attend school, and maintain employment. Discourage patients from smoking, exposing themselves to smoke, and using illegal drugs. Instruct them to avoid unnecessary exposure to infectious agents. However, patients may generally benefit from outdoor activities. Considering the relatively good prognosis of XLA, the physician should encourage patients with this immunodeficiency disease to have a positive mental attitude.
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This patient presented with recurrent otitis and areas of cellulitis in the diaper area. Pseudomonas aeruginosa and Staphylococcus aureus were isolated from the skin lesions. Autoimmune hemolytic anemia and autoimmune neutropenia were confirmed based on the presence of autoantibodies. The patient has a mutation on exon 15, A504T, which changed an asparagine residue to a valine residue.
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Bruton agammaglobulinemia (ie, X-linked agammaglobulinemia [XLA]) in brothers. XLA was diagnosed in the less-robust younger brother when he presented with neutropenia and typhlitis. The older brother, with a history of 7 episodes of pneumonia, was then evaluated and diagnosed with XLA. In both brothers CD19- B cells were less than 1%; this finding is consistent with XLA.
Tables
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 |
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 |
