Further Outpatient Care
New infections can usually be medically managed on an outpatient basis, and appropriate cultures, if indicated, can usually be obtained in the clinical setting. Extensive diagnostic tests including CSF analyses with polymerase chain reaction (PCR) for viral genomes, neuroimaging, and electrophysiologic studies need to be pursued to evaluate for infectious or autoimmune complications.
If indicated, blood samples should be obtained to detect viral RNA or DNA, and liver function tests should be performed to evaluate and to monitor hepatitis. Other infections require follow-up on an outpatient basis.
Frequent monitoring of the patient's pulmonary status is important because the main long-term complication continues to be chronic lung disease. Pulmonary lung function should be assessed regularly, and high-resolution CT scans of the lungs should be performed since bronchiectasis can develop (even in patients on chronic IVIG therapy). If end-stage lung disease develops, lung transplantation has been performed in patients with agammaglobulinemia using intensive IVIG administration (every 48 h during the first 10 d after transplant).
The medical provider is responsible for withholding live viral vaccines. The administration of the live-attenuated oral poliovirus vaccine can cause progressive and fatal meningoencephalitis, as can wild-type enteroviruses. Other live-attenuated vaccines are also contraindicated, although they have not caused such devastating infection.
Avoid live viral vaccines for patients with agammaglobulinemia and any siblings or other children in the household because the attenuated virus is excreted and poses a threat to immunodeficient patients. If the patient has been exposed to a live viral vaccine, or if the live poliovirus has been given, obtain a stool culture to determine if the patient has the attenuated virus. Although most laboratories can determine the presence of an enterovirus, poliovirus identification requires sending the viral specimen to a state referral laboratory. Administer intravenous immunoglobulin (IVIG) and maintain serum immunoglobulin (Ig)G levels higher than 500 mg/dL.
Further Inpatient Care
Hospitalization has become unusual for patients with Bruton agammaglobulinemia, formally termed X-linked agammaglobulinemia (XLA), because home health organizations can provide intravenous antibiotics, pulmonary care, and nutritional interventions on an outpatient basis. Ig replacement therapy with either IVIG administered in outpatient clinics or SCIG at home to minimize interruptions of daily living is the mainstay of medical treatment.
The rationale for hospitalizing patients with XLA who are receiving IVIG replacement is usually to provide an adequate workup of a puzzling infection, to manage severe gastrointestinal issues, to address acute pulmonary decompensation in the presence of chronic pulmonary disease, or to assess and treat severe autoimmune disorders.
Compared with others, patients who are treated have fewer acute overwhelming infections that require hospitalization.
Successful cure has been reported using stem cells from either cord blood or bone marrow from histocompatibility leukocyte antigen (HLA)–matched siblings. [60]
Inpatient & Outpatient Medications
Administer IVIG to every patient with agammaglobulinemia. In rare circumstances (eg, temporary lack of venous access), IMIG can be given. Subcutaneous administration of IVIG is an option depending on individual preferences. A survey revealed that 90% of 1243 (1119) patients with primary immunodeficiencies in 16 countries receive IVIG in an inpatient setting, whereas 7% (87) are treated with subcutaneous Ig (SCIG), mainly at home. [61] However, this survey was performed before the SCIG preparation was available in the US.
Because these patients risk developing unusual infections, attempt to identify any pathogens in either the respiratory or gastrointestinal tracts. More modern techniques using polymerase chain reaction (PCR) helped diagnose Mycoplasma pneumoniae osteomyelitis in a patient with hypogammaglobulinemia with repeatedly sterile pus cultures.
For patients to have refractory Campylobacter jejuni infection longer than 2 years is not unusual, despite therapy with various antibiotics and IVIG preparations.
In patients with respiratory symptoms, analyzing bronchial samples obtained during bronchoscopy using traditional culture as well as PCR may help determine the various viruses and bacteria present.
See Medical Care and Medication.
Transfer
Most clinical immunologists believe that they should usually manage clinical illnesses related to XLA and other primary immunodeficiency diseases because these illnesses are rare and their complications are rarer still.
Generally, primary care physicians who treat patients with XLA and other primary immunodeficiency diseases must have a special interest in immunology and adequate experience in managing these complex problems.
Deterrence/Prevention
Prenatal diagnosis in families known to carry a mutated gene may allow better preparation for the infant's care by the family and the physician.
In families in which a male is diagnosed with XLA, females may wish to undergo evaluation to determine if they are carriers; if they are, genetic counseling regarding future pregnancies can be very beneficial.
Certainly, assessment of B and T cells with flow cytometry is important for an infant at risk before infections develop.
Gene therapy is not yet available for XLA. However, encouraging results using retroviral-mediated gene transfer have been recently reported in a murine model of XLA.
Because patients continue to have improved outcomes, stem cell transplantation is not considered appropriate because of its risk and need for aggressive immunosuppression.
Complications
Major complications are caused by frequent or recurrent infections that result in chronic pulmonary disease and/or chronic enteroviral infection of the CNS.
All of the complications (such as pneumonia, otitis media, and diarrhea) before immunoglobulin replacement therapy was started were reduced, except sinusitis and conjunctivitis. Although most children with XLA develop recurrent bacterial respiratory tract infections during infancy, 20% are diagnosed in children aged 3-5 years, reflecting the widespread use of antibiotics. Unfortunately, permanent damage to the lungs with bronchiectasis may have already occurred. [62] This could be reflected in continued decline in pulmonary function testing. [63] However, increasing the dose may blunt this decline.
The presence of bronchiectasis has also been found to correlate with continued risk for developing pneumonia despite immunoglobulin replacement therapy. [64] A recent report indicates that the development of chronic lung disease was significantly related to age at diagnosis and inappropriate treatment. [65] However, even with immunoglobulin replacement therapy, 38.4% of XLA patients continued to experienced pneumonia and respiratory problems. [66, 67]
Recurrent infections may eventually cause either obstructive disease or combined obstructive and restrictive lung disease. IVIG treatment, aerosol treatments with bronchodilators, and chest physiotherapy, such as postural drainage, may prevent further damage in these patients. No good studies have examined the effectiveness of aerosol treatments in these patients, although one may speculate that mobilization of secretions should help. Similarly, no good studies have examined the usefulness of prophylactic antibiotics, either systemically or topically (ie, aerosolized).
Chronic sinusitis may also result from repeated infections and subsequent structural changes. Chronic ear infections may result in hearing loss.
Autoimmune diseases (eg, inflammatory bowel disease, atrophic gastritis, pernicious anemia) are also observed in patients. Other noninfectious complications that are particularly prevalent include autoimmune disorders such as arthritis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, and autoimmune neutropenia. One center reported that 26.7% of XLA patients have developed neutropenia. [68] There have been attempts to treat with granulocyte colony-stimulating factor (filgrastim). [69] Treatment may also consist of increasing the dose of immunoglobulin replacement and/or steroids or rituximab. [70] A dermatomyositis syndrome has been frequently reported in boys whose past treatments did not include IgG at the high doses currently administered. See section on History.
Reports that showed progressive neurodegeneration in patients with primary immunodeficiency on IVIG treatment are concerning. [71, 72] Extensive diagnostic tests including CSF analyses with PCR for viral genomes, neuroimaging, and electrophysiologic studies need to be pursued to evaluate for infectious or autoimmune complications.
Sensorineural hearing loss may be increased in patients with antibody deficiency (both XLA and CVID) and suggest regular audiologic evaluation. [73]
Eczema and asthma are more frequent in these patients than in immunocompetent individuals.
Patients with low or absent immunoglobulin levels have increased risk of malignancy, especially in the lymphoreticular and GI organs, which may be the result of altered immune surveillance. However, the risk for XLA appears to be much less than the other immunodeficiency syndromes. There has been a report on multiple neoplasms in the GI tract [38] and gastric adenocarcinomas. [74]
Attempts to correlate clinical outcome with severity of various mutations have not been successful. [75] Early diagnosis and treatment continue to result in the best outcome.
Prognosis
IVIG treatment has increased the survival rates of patients with XLA. Interestingly, patients with XLA who receive early and adequate IgG replacement seem to do better than patients with other causes of hypogammaglobulinemia and CVID. Comparisons of XLA and CVID have shown that patients with XLA incur less severe chronic pulmonary disease, less devastating hepatitis C infection (acquired through intravenous immunoglobulin and other blood products), and little risk for malignancy.
The development of chronic lung disease is significantly related to age at diagnosis and inappropriate treatment. [65] However, even with immunoglobulin replacement therapy, 38.4% of patients may continue to experienced pneumonia. [67] Although patients continue to die from chronic pulmonary disease, some now survive into the fifth and sixth decades of life. The development of bronchiectasis despite immunoglobulin replacement therapy in XLA has been well documented. [64, 76]
Patients who begin IVIG replacement therapy when they are younger than 5 years have had prolonged survival and decreased morbidity and mortality rates.
Men with XLA have survived into the fifth decade of life despite suboptimal immunoglobulin replacement because IVIG did not become available until the mid 1980s. The oldest reported patients with XLA are in the sixth decade of life. [77]
Other causes of mortality include complications of colitis and liver disease.
Predominant serious viral infections are enteroviral and may involve the attenuated vaccine strains of poliovirus. Chronic enteroviral CNS infection is the major factor in severe outcomes. Patients with XLA adequately manage other viruses such as measles and varicella. Herpes simplex infections are more likely to be recurrent, and the common wart can be difficult to control.
A theoretical concern is that the frequency of malignancies may increase as the population of patients with XLA ages because the incidence of malignancies increases in older patients with other primary immunodeficiencies. Examples include X-linked hyper-IgM disease, CVID, and Wiskott-Aldrich syndrome, all of which involve antibody deficiencies. However, whether the risk of malignancy is due to the deficiency of antibody or due to other immune dysregulation that accompanies these disorders is not clearly known. Case reports of certain neoplasms, such as colorectal neoplasms, [38] suggest the need for colorectal screening in patients with XLA. GI adenocarcinomas are not unusual. [74]
Despite these health concerns, measurement of quality of life indicates that these patients perceive a higher quality than those with rheumatological disorders, although both groups were lower than healthy controls. [78]
Patient Education
Patients and families must understand the need to recognize and treat infections early.
Recognition of the disease can be difficult because of the subtle presentation of infections caused by the poor inflammatory response compared with that of an immunocompetent host. IVIG replacement may also lull patients into delaying medical care because of both their emotional reliance on IVIG and because of the slowly progressive manifestation of infection, compared with the acute overwhelming presentation in an individual with XLA who does not receive treatment.
Physicians can overcome the tedious nature of chronic pulmonary care and the difficulty in using inhalers by repeating patient education every 6 months, or even more often, as in patients with asthma. Persuading adolescents to maintain these therapies is particularly difficult because they may believe that the compliance activities may cause them to lose the acceptance of their peers.
The Immune Deficiency Foundation is an important resource for education and support for patients and families with any primary immunodeficiency disease. For consultation, the foundation can be reached at 1-877-666-0866. The foundation's mailing address is 25 W Chesapeake Ave, Suite 206, Towson, MD 21204. Some states have local chapters.
The Jeffrey Modell Foundation at 747 3rd Ave, New York, NY 10017, also provides educational support and raises funds for research. The foundation can be reached at 1-800-JEFF-855.
For additional information on related diseases and conditions, see the articles Agammaglobulinemia and B-Cell and T-Cell Combined Disorders.
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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 |
