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Combined B-Cell and T-Cell Disorders Workup

  • Author: Francisco J Hernandez-Ilizaliturri, MD; Chief Editor: Emmanuel C Besa, MD  more...
Updated: Apr 14, 2015

Laboratory Studies

The diagnosis of SCID should be suspected in children with any of the following conditions:

  • Unexplained lymphopenia
  • Failure to thrive
  • Chronic diarrhea
  • Recurrent severe episodes of RSV, HSV, VZV, measles, influenza, or parainfluenza
  • A family history of SCID

Suspected patients require complete evaluation of specific humoral and cellular immunity, which includes measurement of immunoglobulin levels, antibody titers, lymphocyte subsets, and assessment of T-cell function. This can be done via evaluating the responses to mitogens in vitro.

There is no population screening for SCID at present. The probable diagnosis of SCID is based on the following:

  • A T-cell count less than 20% of the lymphocytes, an absolute lymphocyte count of less than 3,000 cells/mm 3, and a response to mitogens of less than 10% of the control or maternal T cells in the circulation
  • At this point, establish a molecular diagnosis and also consider the sex, family history, and phenotype of the patient.
  • Quantitative measurement of the serum immunoglobulins and IgG subclasses is necessary to confirm the diagnosis of B-cell deficiency. If, despite normal results, humoral immunodeficiency is suggested, the antibody response to specific antigens (polysaccharide or protein antigens) should be evaluated further. In patients with SCID presenting with recurrent infections in the first months of life, immunoglobulin levels are not helpful in the diagnosis, owing to the presence and persistence of maternal antibodies.

levels of serum immunoglobulin are determined by serum protein electrophoresis.

  • Quantitative methods are used for the precise measurement of each immunoglobulin isotype. Enzyme-linked immunosorbent assays (ELISAs) are used for IgE quantitation.
  • Compare values to age-standardized reference ranges for each laboratory. The following are examples of values that are 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, the level is less than 200-250 mg/dL. levels of the other immunoglobulins vary depending on the underlying disease.
  • Immunoglobulin subclass deficiency is defined as a decrease of an IgG subclass greater than 2 standard deviations (SDs) below the normal mean for age.

Antibody response after immunization may be absent.

  • Check the antitetanus/diphtheria antibodies (IgG1), antipneumococcal polysaccharide antibodies (IgG2), and antirespiratory virus antibodies (IgG3) if the titers for the total immunoglobulins are within the reference ranges and the patient is unable to produce antibodies to specific antigens.
  • Antibody response is evaluated by measuring antitetanus and antipneumococcal titers 3-4 weeks after vaccination; a rise of 4-fold for antitetanus and 2-fold for antipneumococcal titers is considered normal.

The absence of isohemagglutinins is a significant finding that is suggestive of an immunoglobulin production problem. Evaluate IgM antibodies to A and B blood group antigens (isohemagglutinins) if the other test findings are within reference ranges and the patient is unable to mount a response to specific antigens.

Peripheral blood lymphocyte levels should be measured.

  • The lymphocyte count is higher in infancy and childhood than in adulthood. An absolute lymphocyte count of less than 280 per microliter (ie, 2 SDs below the mean) is abnormal.
  • The association of a low lymphocyte count with recurrent infections is very suggestive of immunodeficiency.

Lymphocyte phenotyping using flow cytometry analysis is the next step. The absolute number of B, T, and NK cells is more useful than percentages.

Measuring T-lymphocyte numbers and function may be necessary. Lymphocyte activation (CD45 RA/RO isoformic antigens) and T-cell receptor phenotype (TCR ab/gd lineage) determination may provide additional information regarding the type of immunodeficiency. For example, Omenn syndrome is characterized by a high number of T cells carrying TCRgd or CD45+. Determination of the helper (CD4) to suppressor (CD8) T-cell ratio is sometimes useful.

Cutaneous delayed-type hypersensitivity testing is used to evaluate the anamnestic response of cellular immunity to previously encountered antigens.

  • The test results are not reliable in children younger than age 1 year, and the response is frequently suppressed following viral and bacterial infections and after glucocorticoid therapy.
  • The results are determined by measuring the induration 48-72 hours following an intradermal injection of 0.1 mL of tetanus toxoid (at 1:100 dilution, 0.2 Loeffler U/0.1 mL), mumps skin test antigen, candidal antigen (at 1:100 dilution; if no reaction is present, use 1:10 dilution), tuberculin (0.1 mL containing 2-10 IU of purified protein derivative [PPD]), and trichophytin (1:30 dilution).
  • The test result is considered positive if the induration is greater than 5 mm (or >2 mm in children).
  • This test can be complemented by in vitro study of lymphocyte proliferation to different mitogens.

Results related to specific disorders are as follows:

  • XHM
    • The IgM measurement is markedly increased to levels frequently higher than 1000 mg/dL. Note:  Normal levels do not exclude the diagnosis (in a study, normal levels were present in 29 of 55 patients with genetically proven XHM[12] ). IgG, IgA, and IgE levels and the number of lymphocytes bearing these antibodies are decreased. An 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 a normal T-lymphocyte count. Chronic neutropenia may be present in some patients.
  • ADA deficiency
    • The erythrocyte deoxy-ATP level is increased in patients with ADA deficiency. The values in carriers are half to two thirds of the normal values of erythrocyte deoxy ATP. Lymphopenia is more severe than in other SCID syndromes (ie, < 500/μ L). Although the number of B and NK cells is decreased, their function is quasinormal, and they normalize completely after bone marrow transplantation without pretransplantation chemotherapy.
  • RAG1 and RAG2 deficiency
    • B and T lymphocytes are completely absent. NK cells are the only circulating lymphocytes. Immunoglobulin levels are severely decreased.

Imaging Studies

See the list below:

  • Chest radiography
    • Sometimes, recurrent or chronic infections may lead to abnormal chest radiographic findings, such as interstitial infiltrates, bronchiectasis, emphysema, and scarring. Note: Normal chest radiographic findings do not exclude the presence of structural abnormalities.
    • A very common finding in SCID can be absence of a thymic shadow. (DiGeorge syndrome and other T-cell defects may also lack thymic tissue, but the presence of thymic tissue does not exclude SCID. Moreover, patients with SCID who have mutations in ZAP70 or CD3 typically have normal-sized thymuses.)
    • Patients with ADA deficiency typically show cupping and flaring of the costochondral junctions.

Other Tests

For a prenatal diagnosis, restriction fragment length polymorphism (RFLP)can help detect genetic defect carriers of XHM, WAS, and ADA deficiency using fetal blood, amnion cells, or chorionic villus tissue. Umbilical cord blood can be used in the prenatal diagnosis of some of these disorders.

T cells are absent in persons with XSCID. B cells and T cells are absent in patients with autosomal recessive SCID. "Bald" lymphocytes found on scanning electron microscopy are diagnostic of WAS. Red blood cell ADA is decreased in fetuses with ADA deficiency.

ADA deficiency can be evaluated by demonstrating the following:

  • Absent ADA levels in lysed erythrocytes
  • A marked increase in dATP levels in erythrocytes
  • A significant decrease in ATP concentration in red blood cells
  • Absent or extremely low levels of N-adenosylhomocysteine hydrolase in red blood cells
  • An increase in 2'-deoxyadenosine in urine and plasma

In AT, chromosomal karyotyping should reveal reciprocal translocations between chromosomes 7 and 14. Chromosomal instability testing is done to confirm AT and NBS to assess spontaneous and induced breakage. Diagnostic findings are absence or dysfunction of the ATM protein and mutations in the ATM gene.



See the list below:

  • Bronchoscopy should be performed frequently for recurrent pulmonary infections.
  • Endoscopic biopsies should be performed to look for the extent and to identify the cause of the diarrhea.
  • Lymph node biopsy is not necessary for the diagnosis, although findings may indicate a paucity of T- and B-cells and a lack of germinal centers [15]
Contributor Information and Disclosures

Francisco J Hernandez-Ilizaliturri, MD Associate Professor of Medicine, Department of Medicine, Assistant Professor of Immunology, Department of Immunology, Roswell Park Cancer Institute, University of Buffalo State University of New York School of Medicine and Biomedical Sciences

Francisco J Hernandez-Ilizaliturri, MD is a member of the following medical societies: American Association for Cancer Research, American Society of Hematology

Disclosure: Nothing to disclose.


Issam Makhoul, MD Associate Professor, Department of Medicine, Division of Hematology/Oncology, University of Arkansas for Medical Sciences

Issam Makhoul, MD is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

David Claxton, MD Professor of Medicine, Department of Internal Medicine, Section of Hematology-Oncology, Hershey Medical Center, Pennsylvania State University College of Medicine

Disclosure: Nothing to disclose.

Mohammad Muhsin Chisti, MD, FACP Assistant Professor of Hematology and Oncology, Karmanos Cancer Institute, Michigan State University College of Human Medicine

Mohammad Muhsin Chisti, MD, FACP is a member of the following medical societies: American College of Physicians, American Medical Association, American Society of Clinical Oncology, American Society of Hematology, Medical Society of the State of New York

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Marcel E Conrad, MD Distinguished Professor of Medicine (Retired), University of South Alabama College of Medicine

Marcel E Conrad, MD is a member of the following medical societies: Alpha Omega Alpha, American Association for the Advancement of Science, American Association of Blood Banks, American Chemical Society, American College of Physicians, American Physiological Society, American Society for Clinical Investigation, American Society of Hematology, Association of American Physicians, Association of Military Surgeons of the US, International Society of Hematology, Society for Experimental Biology and Medicine, SWOG

Disclosure: Partner received none from No financial interests for none.

Chief Editor

Emmanuel C Besa, MD Professor Emeritus, Department of Medicine, Division of Hematologic Malignancies and Hematopoietic Stem Cell Transplantation, Kimmel Cancer Center, Jefferson Medical College of Thomas Jefferson University

Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American Society of Clinical Oncology, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, New York Academy of Sciences

Disclosure: Nothing to disclose.


James O Ballard, MD Kienle Chair for Humane Medicine, Professor, Departments of Humanities, Medicine, and Pathology, Division of Hematology/Oncology, Milton S Hershey Medical Center, Pennsylvania State University College of Medicine

James O Ballard, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, and American Society of Hematology

Disclosure: Nothing to disclose.

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Table 1. Classification of SCID
Pathophysiology Cells Affected Inheritance Genes Involved
Premature cell death T, B, NK AR ADA
Defective cytokine–dependent survival signaling T, NK AR

γ c type-XL

JAK3, IL7RA (T cells only), γ c
Defective V(D)J rearrangement T, B AR RAG1, RAG2, Artemis
Defective pre-TCR and TCR signaling T AR CD3 δ, CD3 ζ, CD3 ε,


AR = autosomal recessive; JAK3 =Janus tyrosine kinase 3; RAG1, RAG2 = recombinase activating gene 1 and 2, respectively; TCR = T-cell receptor; XL = X-linked; V(D)J = variable diversity joining.
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