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Pediatric Bruton Agammaglobulinemia Workup

  • Author: Terry W Chin, MD, PhD; Chief Editor: Harumi Jyonouchi, MD  more...
 
Updated: May 07, 2014
 

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 with 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.

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.

Confirmation of XLA involves molecular diagnostic studies to measure the amount of Btk protein levels in platelets or monocytes and sequence analysis of the Btk gene. If sequencing does not detect a Btk mutation in a patient with absent Btk protein deletion/duplication analysis should be performed to detect mutations occurring outside the coding regions such as mutations in the promoter region. Such a mutation has been described which resulted in defective binding of the transcription factor PU.1, leading to defective transcription of Btk. However, a small subset of patients with XLA have normal protein expression. Additionally, detection of a mutation in Btk gene does not always result in phenotypic XLA.

A definitive diagnosis for XLA can be assumed in any male subject with less than 2% CD19+ cells and 1 of the following: (1) a mutation in Btk, (2) absent Btk mRNA on Northern blot analysis, (3) absent Btk protein in monocytes or platelets; and (4) maternal male cousin, uncles, or nephews with less than 2% CD19+ cells. Patients meeting these criteria account for approximately 85% of cases of agammaglobulinemia. About 5-10% have mutations in genes associated with the autosomal recessive forms. In the remaining 5% of cases, an ill-defined defect is likely because normal levels of Btk protein are seen.

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

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.

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

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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 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.[42]

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 Clinical Professor, Department of Pediatrics, University of California, Irvine, School of Medicine; Associate Director, Cystic Fibrosis Center, Attending Staff Physician, Department of Pediatric Pulmonology, Allergy, and Immunology, Memorial Miller Children's Hospital

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 Federation for Clinical Research, American Thoracic Society, California Society of Allergy, Asthma and Immunology, California Thoracic Society, Clinical Immunology Society, Los Angeles Pediatric Society, Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

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.

Chief Editor

Harumi Jyonouchi, MD Faculty, Division of Allergy/Immunology and Infectious Diseases, Department of Pediatrics, Saint Peter's University Hospital

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 Pediatric Research, Society for Mucosal Immunology

Disclosure: Nothing to disclose.

Additional Contributors

James M Oleske, MD, MPH François-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology and Infectious Diseases, Department of Pediatrics, Rutgers New Jersey Medical School; Professor, Department of Quantitative Methods, Rutgers 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 Hospice and Palliative Medicine, American Association of Public Health Physicians, American College of Preventive Medicine, American Pain Society, Infectious Diseases Society of America, Infectious Diseases Society of New Jersey, Medical Society of New Jersey, Pediatric Infectious Diseases Society, Arab Board of Family Medicine, American Academy of Pain Management, National Association of Pediatric Nurse Practitioners, Association of Clinical Researchers and Educators, American Academy of HIV Medicine, American Thoracic Society, American Academy of Pediatrics, American Public Health Association, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society

Disclosure: Nothing to disclose.

Acknowledgements

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.

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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 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
Table 2. Immune Globulin, Subcutaneous
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
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