Agammaglobulinemia Workup

Updated: Jul 08, 2019
  • Author: Donald A Person, MD, FAAP, FACR; Chief Editor: Harumi Jyonouchi, MD  more...
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Workup

Laboratory Studies

In patients with agammaglobulinemia, or hypogammaglobulinemia, all circulating immunoglobulin (Ig) levels (IgG, IgA, IgM, IgE) are low. The physician must compare the patient's specific levels with age-appropriate controls.

Serum IgG levels lower than 100 mg/dL should arouse concern. In some patients with X-linked agammaglobulinemia (XLA), IgG levels may be as high as 200-300 mg/dL. This does not necessarily exclude a diagnosis of XLA.

Patients are also unable to make specific antibody responses. They usually revealed decreased antibody levels against common childhood vaccine antigens such as diphtheria, pertussis, varicella, hepatitis B, and H influenzae.

In young infants (< 6 mo), because the serum IgG level is unreliable secondary to the presence of a maternal antibody, the physician cannot rely on Ig level determinations. Patients' families also have anxiety about a diagnosis of possible immunodeficiency. Determining diphtheria and tetanus antibody titers prior to vaccine administration and after administration in 3-4 week intervals to assess responses. If specific diphtheria and tetanus levels rise, this indicates that the infant is able to produce antigen-specific antibody, rendering agammaglobulinemia (or any other B-cell deficiency) unlikely.

In one study of premature infants with hypogammaglobulinemia normalization of IgG occurred at a mean age of 7.2 months. [64] The concomitant occurrence of low IgM, impaired antibody response and low B-cell counts was predictive of persistence of hypogammaglobulinemia beyond 5 years of age and chronic lung disease. [65]

Functional IgM production can be measured by checking isohemagglutinin titers.

Note that pre–B cells can produce IgM in detectable quantities, including IgM autoantibodies particularly directed against hematopoietic cells (typical antirhesus [anti-Rh] in autoimmune hemolytic anemia, antineutrophil antibodies).

Because B-cell maturation is arrested, patients lack mature B lymphocytes in their peripheral blood or tissue. Performing flow cytometry to analyze B- and T-cell marker expression is necessary. This can be assessed by staining for B-lymphocyte–specific surface cell markers by flow cytometry.

Most laboratories should be able to perform this test because similar technology examines the T-lymphocyte markers of CD4 and CD8 used in assessing HIV infection. However, laboratory personnel must be informed that B-lymphocyte–specific monoclonal antibodies (CD19 and/or CD20) should be used for analysis.

Reduced numbers of peripheral blood B lymphocytes suggest the diagnosis, no matter what the age of the patient.

Mutational analysis must be performed to confirm the specific type of agammaglobulinemia.

In addition, plasma cells and B lymphocytes in lymphoid follicles and in germinal centers of lymph nodes may be lacking. Because intestinal biopsy may be obtained to evaluate patients with chronic diarrhea, examination for hypoplastic Peyer patches in the lamina propria of intestinal mucosa may be helpful in diagnosing agammaglobulinemia.

Patients with growth hormone deficiency have a deficient growth hormone response to insulin, arginine, or levodopa (L-dopa). Plasma somatomedin levels are also reduced.

Continued examination for infection by various pathogens to explain various clinical symptoms (ie, respiratory, GI, arthritic, neurologic complaints) is needed. Persistence of pathogens in immunodeficient patients has been well-documented. For example, rhinovirus is the most common respiratory virus and can persist for up to 4 months. [66]

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Imaging Studies

No radiological findings are specific for agammaglobulinemia, although it is suggested by an absence of adenoidal tissue (eg, adenoidal tissue in lateral head films to evaluate chronic sinusitis). Chest radiography findings of unexplained bronchiectasis should also lead to an evaluation of the patient's immune status.

CT scanning of the sinuses and the lungs is more effective than plain radiography in documenting disease progression in these locations. High-resolution CT scanning of the chest is helpful to delineate the extent of lung damage. One study found bronchiectasis in 58% patients with agammaglobulinemia. [67]

Their presence appears to increase the likelihood of pneumonia and decreasing lung function.

Sinus CT examinations may be required as clinically needed. [67]

Some physicians advocate using MRI of the brain in patients with agammaglobulinemia or hypogammaglobulinemia who develop unexplained neurological symptoms and signs of meningeal inflammation, despite extensive investigation of cerebrospinal fluid (CSF), including polymerase chain reaction (PCR) analyses.

Delayed bone age is evident in patients with growth hormone deficiency.

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Other Tests

The progressive nature of chronic lung disease makes pulmonary function tests (PFTs) essential in XLA. These tests include spirometry, diffusion capacity tests, and lung volume tests. They are recommended annually. Children younger than 5 years may not be able to reliably undergo these tests but some centers perform infant PFTs and/or impulse oscillometry.

PFT findings are evaluated upon diagnosis because the literature suggests that decreased parameters upon diagnosis of hypogammaglobulinemia correlate with chronic and progressive pulmonary disease such as bronchiectasis. [68] Both restrictive and obstructive patterns of chronic lung disease may occur in antibody deficiency diseases.

Due to their recurrent otitis media, conductive hearing loss can be seen in about 73%. [69]

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Procedures

Bronchoscopy is an important adjunct for diagnosing pulmonary infections because it obviates most contamination with mouth flora and because it can be used to procure sputum from infants and others who are unable to voluntarily cough it out.

Examination of the GI tract using endoscopy and colonoscopy is necessary to assess the extent of inflammatory bowel disease. The biopsy results, videotapes, and photographs obtained from these procedures can be used to delineate the disease.

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Histologic Findings

Findings of hypoplastic or absent tonsils, adenoids, and lymph nodes in tissue usually rich in B lymphocytes suggest the diagnosis.

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