Pediatric Bruton Agammaglobulinemia Workup

  • Author: Terry W Chin, MD, PhD; Chief Editor: Harumi Jyonouchi, MD   more...
 
Updated: Sep 28, 2010
 

Laboratory Studies

Measurement of IgG using quantitative techniques such as nephelometry supports the diagnosis of X-linked agammaglobulinemia (XLA) when the IgG level is less than 100 mg/dL. Confirmation of XLA requires low (< 1%) or absent expression of CD19+ lymphocytes, low or absent expression of the heavy-chain µ on the surface, and the presence of normal-to-increased numbers of mature T lymphocytes.

Quantitative measurements of IgG, IgM, IgA, and IgE are readily available and inexpensive and require little blood.

IgG levels are less than 100 mg/dL in most patients with XLA who are aged 6 months or older. However, in some patients with XLA, IgG levels may be as high as 200-300 mg/dL. Unlike IVIG, IMIG administration does not significantly affect this level.

IgM and IgA are usually undetectable in patients of any age. In patients with XLA, levels are usually far below age-related reference ranges; however, in mild cases of XLA and in other antibody deficiencies, Ig levels must be carefully compared with age-related reference ranges.

IgG subclass levels are not usually required because the total IgG is severely deficient. Determination of functional antibody levels as noted below is more appropriate in the rare case in which the total IgG level is indeterminate.

Fluorocytometric analysis (ie, flow cytometry) of B- and T-lymphocyte markers must be performed to confirm XLA diagnosis.

Absent or low (< 1%) CD19+ B cells confirm the diagnosis of XLA in male patients. Numbers of CD4+ and CD8+ T cells are often increased or sometimes normal, but they are rarely low. Low T-cell percentages suggest a diagnosis of SCID or another T-cell disorder. In an infant or child, the presence of low absolute T-cell numbers suggests a form of SCID, not XLA. An inverted CD4/CD8 T-cell ratio occurs in some types of SCID and in human immunodeficiency virus (HIV) infection.

Markers for surface Ig expression are also customarily obtained using fluorocytometric analysis. Antibodies directed against the heavy-chain constant region of IgG, IgA, IgM, and IgD are used to detect these isotypes. The first 2 are expected to be absent, although some expression of IgM and IgD may be present. Cells that express IgM alone, without IgD, are considered less differentiated and, therefore, are more likely to be present.

Specific IgG antibody responses to T-cell–dependent and T-cell–independent antigens should also be measured.

Because the serum IgG level is contaminated from the presence of maternal antibody (due to transplacental transmission) in young infants (< 6 mo), the physician cannot rely on Ig level determinations. However, obtaining specific serum diphtheria and tetanus antibody levels before and after (3-4 wk) a diphtheria, pertussis, and tetanus vaccine is administered is helpful. If specific diphtheria and tetanus levels are increased, the infant is able to produce antigen-specific antibodies, and XLA is unlikely.

Tetanus, diphtheria, and the conjugated H influenzae type b antigens require T-cell–dependent IgG antibody responses. Unconjugated 23-valent pneumococcal vaccine elicits a T-cell–independent IgG antibody response.

IgM antibody function is assessed by measuring isohemagglutinin titers, antibodies directed against blood group A and B antigens. These antibody levels are age-related.

Measurement of Btk activity firmly establishes the diagnosis. However, in the setting of low serum Ig levels and absent mature B lymphocytes, this testing is probably not necessary.

Mutational analysis can also be performed; however, the clinical significance of the results is not certain unless population studies are performed.[26, 12]

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Imaging Studies

Plain radiographic studies may contribute to the diagnosis of XLA but are not an essential part of the workup. Plain radiography of the head may reveal the absence of tonsillar and adenoid tissues. Chest radiographs may be used to diagnose more extensive infection or a chronic infection that is not clinically apparent.

Imaging studies are primarily used to assess chronic sinopulmonary disease.

CT scanning of the sinuses and the lungs is more effective than plain radiography in documenting disease progression in these locations. One study found bronchiectasis in 58% patients with agammaglobulinemia.[27]

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

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Other Tests

The slowly 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.

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.[28]

Both restrictive and obstructive patterns of chronic lung disease may occur in antibody deficiency diseases.

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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

Inflammatory responses are the most common findings in tissue biopsy samples obtained to evaluate infection.

Inflammation is usually nonspecific and is not helpful in distinguishing specific infectious agents.

The presence of pleocytosis in the spinal fluid is a special circumstance in which inflammation is associated with specific infection by an enterovirus.

Lymphoid tissues lack germinal centers, and plasma cells are absent in bone marrow and the lamina propria of the gut.

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Contributor Information and Disclosures
Author

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

Terry W Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, California Thoracic Society, Clinical Immunology Society, and Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

James M Oleske, MD, MPH  François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, New Jersey Medical School

James M Oleske, MD, MPH is a member of the following medical societies: Academy of Medicine of New Jersey, American Academy of Allergy Asthma and Immunology, American Academy of HIV Medicine, American Academy of Hospice and Palliative Medicine, American Academy of Pain Management, American Academy of Pediatrics, American Association of Pediatrics, American Association of Public Health Physicians, American College of Preventive Medicine, American Pain Society, American Public Health Association, American Society for Microbiology, American Thoracic Society, Arab Board of Family Medicine, Association of Clinical Researchers and Educators (ACRE), Infectious Diseases Society of America, Infectious Diseases Society of America, Infectious Diseases Society of New Jersey, Medical Society of New Jersey, National Association of Pediatric Nurse Practitioners, Pediatric Infectious Diseases Society, and Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

John Wilson Georgitis, MD  Consulting Staff, Lafayette Allergy Services

John Wilson Georgitis, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association for the Advancement of Science, American College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society

Disclosure: Nothing to disclose.

David Pallares, MD  Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville

David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology

Disclosure: Nothing to disclose.

Chief Editor

Harumi Jyonouchi, MD  Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School

Harumi Jyonouchi, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Medical Association, Clinical Immunology Society, New York Academy of Sciences, Society for Experimental Biology and Medicine, Society for Mucosal Immunology, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgments

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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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.
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.
Table 1. Immune Globulin, Intravenous
Brand(Manufacturer)Manufacturing ProcesspHAdditives (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 ConcentrationsIgA Content mcg/mL
Carimune NF



(ZLB Behring)



Kistler-Nitschmann fractionation, pH 4 incubation, nanofiltration6.4-6.86% solution: 10% sucrose, < 20 mg NaCl/g proteinLyophilized powder 3, 6, 9, 12%Trace
Flebogamma



(Grifols USA)



Cohn-Oncley fractionation, PEG precipitation, ion-exchange chromatography, pasteurization5.1-6Sucrose free, contains 5% D-sorbitolLiquid 5%< 50
Gammagard Liquid 10%



(Baxter Bioscience)



Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation 4.6-5.10.25 M glycineReady-for-use liquid 10%37
Gammar-P IV



(ZLB Behring)



Cohn-Oncley fraction II/III, ultrafiltration, pasteurization6.4-7.25% solution: 5% sucrose, 3% albumin, 0.5% NaClLyophilized powder 5%< 20
Gamunex



(Talecris Biotherapeutics)



Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation4-4.5Contains no sugar, contains glycineLiquid 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 4.8-5.1Contains sorbitol (40 mg/mL); do not administer if fructose intolerantReady-for-use solution 5%< 10
Iveegam EN



(Baxter Bioscience)



Cohn-Oncley fraction II/III, ultrafiltration, pasteurization6.4-7.25% solution: 5% glucose, 0.3% NaClLyophilized 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 6.4-7.25% solution: 0.3% albumin, 2.25% glycine, 2% glucoseLyophilized 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 pasteurization5.1-610% maltoseLiquid 5%200
Panglobulin



(Swiss Red Cross for the American Red Cross)



Kistler-Nitschmann fractionation, pH 4 incubation, trace pepsin, nanofiltration6.6Per gram of IgG: 1.67 g sucrose,< 20 mg NaClLyophilized powder 3, 6, 9, 12%720
Privigen



(CSL Behring)



pH 4 incubation, octanoic acid fractionation, depth filtration, and virus filtration4.6-510% solution; Preservative-free and sucrose- and maltose-freeReady-to-use solution 10%25
Table 2. Immune Globulin, Subcutaneous
Brand(Manufacturer)Manufacturing ProcesspHAdditivesParenteral Form and Final ConcentrationsIgA Content mcg/mL
Vivaglobin



(ZLB Behring)



Cold ethanol fractionation, pasteurization6.4-7.22.25% glycine, 0.3% NaClLiquid 16% (160 mg/mL)< 50 mcg/mL
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