eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Bruton Agammaglobulinemia: Follow-up

Author: Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Contributor Information and Disclosures

Updated: Sep 3, 2008

Follow-up

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. IVIG can be administered in outpatient clinics or at home to minimize interruptions of daily living. SCIG is an alternate when intravenous access is difficult.
  • 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.²⁶
• Patients with newly diagnosed or suspected antibody deficiencies, including XLA, are commonly identified when they present with acute pneumonias or other overwhelming bacterial infections.
  • These patients may have neutropenia, anemia, and/or thrombocytopenia at the time of severe infections.
  • Search for autoantibodies with these hematologic abnormalities. Cytopenias should not be assumed to represent nonimmune complications of the infection. Autoimmune disorders may require specific intervention with steroids, although this may compromise the effectiveness of IgG transfusion therapy.

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.
• 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. 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).
• An intriguing report from Brazil showed clinical improvement in patients with XLA who were not receiving IVIG replacement therapy but were receiving aggressive respiratory physiotherapy.²⁷
• 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.

Inpatient & Outpatient Medications

• 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.
  • 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.²⁸
  • 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.
  • Autoimmune diseases (eg, inflammatory bowel disease, atrophic gastritis, pernicious anemia) are also observed in patients with agammaglobulinemia or hypogammaglobulinemia.
  • Reports that showed progressive neurodegeneration in patients with primary immunodeficiency on IVIG treatment are concerning.^29,30 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.
• Other noninfectious complications that are particularly prevalent include autoimmune disorders such as arthritis, autoimmune hemolytic anemia, autoimmune thrombocytopenia, and autoimmune neutropenia in patients with hypogammaglobulinemia; these are also reported in patients with XLA.
  • A dermatomyositis syndrome has been frequently reported in boys whose past treatments did not include IgG at the high doses currently administered.
  • 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, especially at the GI level, where multiple neoplasms have been described in XLA.³¹
• Attempts to correlate clinical outcome with severity of various mutations have not been successful.¹⁷ 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. A study of 18 patients with XLA on IVIG showed that they had normal growth and a rate of infection of 4.8 per patient-year, compared with a control population of pediatric patients who had 5.6 infections per patient-year.³²
  • 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.³³
  • Although patients continue to die from chronic pulmonary disease, some now survive into the fifth and sixth decades of life.
  • 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. However, observed cases of malignancies are rare, although they cause significant mortality in other antibody deficiency diseases.

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 eMedicine articles Agammaglobulinemia and B-Cell and T-Cell Combined Disorders.

Miscellaneous

Medicolegal Pitfalls

• One pitfall is the failure to diagnose Bruton agammaglobulinemia, formally termed X-linked agammaglobulinemia (XLA), in a male infant with a family history of XLA.
• The failure to correctly interpret laboratory test findings, such as failing to compare quantitative Ig levels with those in the age-related reference range, may create legal liability. The provider who orders the tests must provide the patient's age to the laboratory.
  • Antibody responses depend on the immunization status of the patient, and, in some cases, they are age-related. Typically, the medical provider rather than the laboratory is responsible for knowing this information.
  • The enumeration of T- and B-lymphocyte populations varies with age and clinical illnesses, especially infections. Therefore, the physician who orders the tests must either know the expected cell distribution based on the patient's condition or seek consultation with someone who does.
• Individuals supervising the IVIG therapy are responsible for monitoring the infusion and for intervening when needed. Theoretically, family members and medical personnel have legal risks in these situations.
• 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.
• The failure to educate the patient about the complications of XLA may be cause for legal action.

Special Concerns

• Patients who require surgical procedures generally receive a dose of IVIG on the day preceding the procedure in an attempt to decrease risk of new infections.
• Opportunistic infections remain rare in patients with XLA. Infections with P carinii and B cepacia have been reported. Invasive fungal infections that typically occur with phagocytic and T-cell disorders are also extremely rare, even in patients who require systemic steroid administration.
• Children must not receive the live attenuated oral poliovirus vaccine because it may 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.
• Unusual infections from animal bites, especially from dogs, have been reported in patients with compromised antibody responses.
• Children with this diagnosis could have a lifelong disease that impacts their families. Care in a center with social worker involvement is desirable. The Immune Deficiency Foundation and the Jeffrey Modell Foundation are examples of organizations that provide social support for families.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Ann O'Neill Shigeoka, MD to the development and writing of this article.

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