eMedicine Specialties > Hematology > Disorders of Lymphocytic Function

Pure B-Cell Disorders: Differential Diagnoses & Workup

Author: Issam Makhoul, MD, Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences
Coauthor(s): David Claxton, MD, Assistant Professor, Department of Internal Medicine, Section of Hematology-Oncology, Hershey Medical Center, Pennsylvania State University; Witold Rybka, MD, Professor of Medicine and Pathology, Penn State Hershey College of Medicine, Director, Bone Marrow Transplant Program, Penn State Hershey Medical Center; Hanan Makhoul, MD, Staff Physician, Department of Internal Medicine, University of Arkansas School of Medicine
Contributor Information and Disclosures

Updated: Nov 4, 2009

Differential Diagnoses

Complement Deficiencies

Workup

Laboratory Studies

• The evaluation of patients with possible B-cell disorders should include a quantitative measurement of serum immunoglobulins and IgG subclasses. If the findings from these studies are within reference ranges and the likelihood remains that the patient has a humoral immunodeficiency, the antibody response to specific antigens (polysaccharide or protein antigens) should be evaluated further. In SCID patients presenting with recurrent infections in the first months of life, immunoglobulin levels are not helpful in the diagnosis because of the persistence of maternal antibodies.
• Levels of serum immunoglobulin
  • Serum protein electrophoresis is appropriate for presumptive diagnosis of hypogammaglobulinemia or monoclonal protein. Quantitative methods are used for the precise measurements of each immunoglobulin isotype. Enzyme-linked immunosorbent assay is used for IgE quantitation.
  • Values should be compared with age-standardized reference ranges for each laboratory. The following ranges are examples of values used for the adult population:
    • IgG1 - 500-1200 mg/dL
    • IgG2 - 200-600 mg/dL
    • IgG3 - 50-100 mg/dL
    • IgG4 - 20-100 mg/dL
    • IgM - 50-150 mg/dL
    • IgA1 - 50-200 mg/dL
    • IgA2 - 0-20 mg/dL
    • IgD - 0-40 mg/dL
    • IgE - 0-0.2 mg/dL
  • In most disorders involving IgG, its level is less than 200-250 mg/dL with variable levels of the other immunoglobulins, depending on the underlying disease.
• Immunoglobulin subclasses: Immunoglobulin subclass deficiency is defined as a decrease of an IgG subclass by more than 2 standard deviations below the normal mean for age.
• Antibody response after immunization
  • This response may be absent. Antitetanus/diphtheria antibodies (IgG1), antipneumococcal polysaccharide antibodies (IgG2), and antirespiratory virus antibodies (IgG3) should be checked if the titers for total immunoglobulins are normal and the patient is unable to produce antibodies to specific antigens.
  • This response may be evaluated by measuring antitetanus and antipneumococcal titers 3-4 weeks after vaccination; a 4- and 2-fold rise, respectively, is considered normal.
• Isohemagglutinins
  • IgM antibodies to A and B blood group antigens (isohemagglutinins) should be checked if the other test results are normal and the patient is unable to mount a response to specific antigens.
  • The absence of isohemagglutinins is a significant finding suggestive of an immunoglobulin production problem.
• Evaluation of cellular immunity (see Combined B-Cell and T-Cell Disorders)
  • Measure peripheral blood lymphocyte levels.
  • Perform lymphocyte phenotyping using flow cytometry.
  • Evaluate T-lymphocyte number and function.
  • Determine the helper-to-suppressor (CD4-to-CD8) T-cell ratio.
  • Assess delayed-type skin hypersensitivity.
• Autoantibodies and antibodies to IgA
  • These occur in more than 20% of patients with IgA deficiency. They are not predictive of adverse reactions to blood products containing IgA.
  • Autoantibodies and antibodies to food antigens (eg, cow milk) may be present in patients with IgA deficiency.
• Results in specific B-cell disorders
  • For XLA, serum immunoglobulin levels are low, with an IgG level of less than 100 mg/dL. Response to immunization is absent. Isohemagglutinins are absent. B-lymphocyte numbers in the peripheral blood are decreased or absent, while T-lymphocyte numbers are normal. Genetic analysis helps make the final diagnosis.
  • For CVID, serum immunoglobulin levels, especially those of IgA and IgG, are low. The immunization response is decreased. The B-lymphocyte count in the peripheral blood is normal in more than 75% of patients. The T-lymphocyte count is normal in most patients, but it may be decreased with a reversal of the CD4-to-CD8 T-cell ratio.
  • For selective IgA deficiency, the serum IgA level is less than 5 mg/dL, with normal IgG and IgM levels. Both IgA1 and IgA2 levels are usually decreased. The IgE level is decreased in 25% of these patients. IgG2 and IgG4 levels may be decreased, especially in patients with sinopulmonary infections. Because IgA deficiency may be a transient phenomenon, IgA and IgG measurements should be repeated after a period of observation. Anti-IgA antibodies are present in more than 20% of patients. Their presence does not correlate with the occurrence of an anaphylactic reaction to IgA-containing blood products. Autoantibodies to the adrenal gland, parietal cells, pancreatic islets, smooth muscle, thyroglobulin, immunoglobulins, and nuclear proteins are observed. Antibodies to food antigens (eg, cow milk) can be observed.
  • For XHM, IgM is markedly increased to levels frequently higher than 1000 mg/dL. Normal levels do not exclude the diagnosis because these have been found in 29 of 55 patients with genetically proven XHM. IgG, IgA, and IgE levels are decreased, as are the numbers of lymphocytes bearing these antibodies. IgM response to antigen exposure is possible, but the IgG and IgA responses are absent or diminished. Cell-mediated immunity is defective in some patients despite normal T-lymphocyte counts. Chronic neutropenia may be present in some patients.
  • For IgG subclass deficiency, one or more IgG subclasses and other immunoglobulin isotypes may be involved. Levels of one or more IgG subclasses may be decreased. Quantitation of the immunoglobulin response to polysaccharide and protein antigens (eg, pneumococcal vaccine, tetanus toxoid) provides more information than simple measurements of IgG subclasses. Total immunoglobulin levels are normal or increased. Antibodies to specific antigens (proteins or polysaccharides) may be defective.
  • For immunodeficiency with thymoma, a decreased IgG level is the most common finding, followed by decreased IgM and IgA levels. Absolute lymphopenia is also common. B-lymphocyte levels in the peripheral blood are frequently decreased. Absolute CD4⁺ T lymphocyte numbers may be decreased, with reversal of the CD4-to-CD8⁺ T-cell ratio. Absent skin hypersensitivity reactions are documented in many cases, with abnormal in vitro lymphocyte proliferation assay findings in some patients. All patients with thymoma should have their immunoglobulin levels quantitated at baseline and then periodically.
  • For IgE hypogammaglobulinemia, the radioallergosorbent test measures serum IgE levels to 60 regional seasonal and nonseasonal allergens and returns a negative finding in persons with this disease. Skin test results to the same allergens are also negative. A decreased IgE level (<2.5 IU/mL) is the only finding in 43% of these patients. Of all cases, 57% are associated with depressed serum levels of other immunoglobulins.
  • For isolated immunoglobulin deficiency (ie, IgM, IgA), IgM or IgA levels are low, whereas the rest of the immunoglobulin levels are normal.
  • For THI, B and T lymphocytes are normal in number and T-cell function is normal. Isohemagglutinin production is normal. Infants produce antitetanus and diphtheria antibodies by age 6-11 months. Immunoglobulin levels normalize by age 2-3 years.
  • For HIE syndrome, most patients have increased IgE, to levels higher than 480 mcg/dL (reference range, <24 mcg/dL). Eosinophilia is common. IgM, IgG, and IgA levels are usually within the reference range. Levels of anti– S aureus IgE and IgM antibodies are markedly higher than matched controls, and levels of anti– S aureus IgG and especially IgA are significantly lower than in controls.
  • For Omenn syndrome, serum IgE levels are increased. The levels of other immunoglobulins are decreased. Hypereosinophilia is observed.

Imaging Studies

• Chest radiographs
  • Most patients with CVID and primary hypogammaglobulinemia develop pulmonary complications that might be visible on chest radiographs.
  • Interstitial infiltrate, bronchiectasis, emphysema or bullae, and scarring may be evident; however, radiographic findings may be normal, and only high-resolution CT (HRCT) scans can reveal the abnormalities.
• High-resolution CT scans
  • HRCT scans may be the criterion standard to study lung abnormalities in these patients.
  • Patients with CVID and primary hypogammaglobulinemia may develop pulmonary fibrosis, bronchiectasis, parenchymal scarring, pleural thickening, and, less commonly, emphysema or parenchymal nodules.
  • Follow-up monitoring with HRCT scans sometimes reveals silent and asymptomatic deterioration despite appropriate IVIG therapy.
  • The role and therapeutic implications of clinical findings derived from this test have been discussed, with some authors recommending intensification of immunoglobulin therapy to achieve higher trough levels.

Other Tests

• Lymph node biopsy: This test reveals the absence of plasma cells, lymphoid follicles, or germinal centers in persons with XLA. In those with XHM, follicles and germinal centers are absent but plasma cells may be identified.
• Intrauterine diagnosis: This can be performed by restriction fragment length polymorphism for X-linked defects.
• Polymerase chain reaction: This may be helpful in the diagnosis of enteroviral meningoencephalitis or JC virus (polyomavirus) infection.
• Brain biopsy may be needed to confirm the diagnosis of these disorders.

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