Immunoglobulin Disorders

  • Diagnosis
  • Algorithms
  • Background
  • Lab Tests
  • References
  • Related Content

Indications for Testing

  • Recurrent infections (eg, sinusitis, otitis media, pneumonia) and/or chronic diarrhea

Laboratory Testing

  • Initial screening
    • General immunodeficiency screening
      • CBC with differential
      • Comprehensive metabolic profile
      • Quantitative serum immunoglobulins (IgA, IgG, IgM)
        • IgG normal but suspicion for deficiency – perform IgG subclass testing
        • Elevated immunoglobulins may require further evaluation including mutation testing to confirm uncommon disorders (eg, hyper-IgM syndrome)
      • Lymphocyte subset analyses – depending on clinical presentation
      • Pre and postvaccination titers – most useful if presentation is solely recurrent sinopulmonary disease, or normal quantitative immunoglobulins
    • Rule out other diseases associated with immunodeficiency
    • Rule out diseases associated with protein losses (eg, protein-losing enteropathy, nephropathy)
  • More specific screening – based on initial screening results
    • Choice of testing based on initial screening results
    • Clinical presentation may require multiple immune system investigations (see Immunodeficiency Evaluation algorithms)
    • Definitive diagnosis, prognostication, and treatment may require genetic testing in consultation with genetic counselor

Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm

Immunodeficiency Evaluation for Chronic Infections in Infants and Children Testing Algorithm

Immunoglobulin deficiencies are the most common primary immunodeficiency.

Epidemiology

  • Incidence – 1/2,000 live births for primary immunodeficiency

Specific Immunoglobulins

  • Structure – 2 heavy chains, 2 light chains
    • Isotype (G, M, A, D, E) – determined by type of heavy chain

Indications for Laboratory Testing

Tests generally appear in the order most useful for common clinical situations.
Click on number for test-specific information in the ARUP Laboratory Test Directory

Immunoglobulins (IgA, IgG, IgM), Quantitative 0050630
Method: Quantitative Nephelometry

Immunoglobulin G Subclasses (1, 2, 3, 4) 0050577
Method: Quantitative Nephelometry

Lymphocyte Subset Panel 6 - Total Lymphocyte Enumeration with CD45RA and CD45RO 0095862
Method: Quantitative Flow Cytometry

Lymphocyte Subset Panel 7 - Congenital Immunodeficiencies 0095899
Method: Quantitative Flow Cytometry

Regulatory T-Cell Panel 2010172
Method: Quantitative Flow Cytometry

Streptococcus pneumoniae Antibodies, IgG (14 Serotypes) 0050725
Method: Quantitative Multiplex Bead Assay

Diphtheria, Tetanus, and H. Influenzae b Antibodies, IgG 0050779
Method: Quantitative Multiplex Bead Assay

Hyper IgM Syndrome Panel, Sequencing (12 Genes) and Deletion/Duplication (10 Genes) 2011154
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations

Not determined or evaluated – mutations in genes not included on the panel; deep intronic and regulatory region mutations; breakpoints for large deletions/duplications; translocations

Deletions/duplications will not be detected in IKBKG or PIK3CD

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude a diagnosis of hyper-IgM syndrome

Primary Antibody Deficiency Panel, Sequencing (35 Genes) and Deletion/Duplication (26 Genes)  2011156
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Limitations

Not determined or evaluated – mutations in genes not included on the panel; deep intronic and regulatory region mutations; breakpoints for large deletions/duplications; translocations

Deletions/duplications will not be detected in IKBKG, LRBA, LRRC8A, PIK3CD, PIK3R1, PLCG2, PRKCD, SH2D1A, or XIAP/BIRC4 genes

Small deletions or insertions may not be detected

Diagnostic errors can occur due to rare sequence variations

Lack of a detectable gene mutation does not exclude a diagnosis of primary antibody deficiency

Additional Tests Available

CBC with Platelet Count and Automated Differential 0040003
Method: Automated Cell Count/Differential

Comments

General screen for suspected immunodeficiency

Comprehensive Metabolic Panel 0020408
Method: Quantitative Ion-Selective Electrode/Quantitative Enzymatic/Quantitative Spectrophotometry

Comments

General screen for suspected immunodeficiency

Monoclonal Protein Detection Quantitation and Characterization, SPEP, IFE, IgA, IgG, IgM, Serum 0050615
Method: Qualitative Immunofixation Electrophoresis/Quantitative Capillary Electrophoresis/Quantitative Nephelometry

Comments

Evaluation for plasma cell dyscrasias

Kappa and Lambda Free Light Chains (Bence Jones Protein), Quantitative, Urine 0050618
Method: Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry

Comments

Evaluation for plasma cell dyscrasias

Alpha-1-Antitrypsin, Quantitative by ELISA, Random Stool 2011041
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Comments

Useful in evaluation of  protein-losing enteropathy

Alpha-1-Antitrypsin Clearance, Quantitative by ELISA, Timed Stool 2011043
Method: Enzyme-Linked Immunosorbent Assay/Quantitative Immunoturbidimetry

Comments

Useful in evaluation of  protein-losing enteropathy

Human Immunodeficiency Virus Types 1 and 2 (HIV-1, HIV-2) Antibodies by CIA with Reflex to HIV-1 Antibody Confirmation by Western Blot 2005377
Method: Qualitative Chemiluminescent Immunoassay/Qualitative Western Blot

Comments

Initial evaluation for HIV

Immunoglobulin A, Saliva 0050525
Method: Quantitative Nephelometry

Comments

Quantify salivary IgA in patients with recurrent upper respiratory infections

Immunoglobulin G 0050350
Method: Quantitative Nephelometry

Immunoglobulin M 0050355
Method: Quantitative Nephelometry

Immunoglobulin D, Serum 0099200
Method: Quantitative Nephelometry

Immunoglobulin E 0050345
Method: Quantitative ImmunoCAP® Fluorescent Enzyme Immunoassay

Immunoglobulin G Subclass 1 0050571
Method: Quantitative Nephelometry

Immunoglobulin G Subclass 2 0050572
Method: Quantitative Nephelometry

Immunoglobulin G Subclass 3 0050573
Method: Quantitative Nephelometry

Immunoglobulin G Subclass 4 0050576
Method: Quantitative Nephelometry

Immunoglobulin G4 by Immunohistochemistry 2005844
Method: Immunohistochemistry

Immunoglobulins, CSF Quantitative 0050631
Method: Quantitative Nephelometry

Immunoglobulin A, CSF 0050341
Method: Quantitative Nephelometry

Immunoglobulin G, CSF 0050670
Method: Quantitative Nephelometry

Immunoglobulin G/Albumin Ratio, CSF 0050680
Method: Nephelometry

Immunoglobulin G, CSF Index 0050676
Method: Quantitative Nephelometry

Immunoglobulin M, CSF 0050356
Method: Quantitative Nephelometry

Humoral Immunity Panel I 0050980
Method: Quantitative Nephelometry/Semi-Quantitative Multiplex Bead Assay

Immunoglobulin A Subclasses (1&2) 0093149
Method: Quantitative Nephelometry

Humoral Immunity Panel II 0050981
Method: Semi-Quantitative Multiplex Bead Assay

Anti-IgA Antibody by ELISA 2003126
Method: Quantitative Enzyme-Linked Immunosorbent Assay

Comments

Test for antibodies to IgA in patients with IgA deficiency and blood transfusion reaction

General References

About Primary Immunodeficiencies - Specific Disease Types. Immune Deficiency Foundation. Towson, MD [Accessed: Nov 2015]

Al-Herz W, Bousfiha A, Casanova J, Chatila T, Conley M, Cunningham-Rundles C, Etzioni A, Franco J, Gaspar B, Holland S, Klein C, Nonoyama S, Ochs H, Oksenhendler E, Picard C, Puck J, Sullivan K, Tang M. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5: 162. PubMed

Ballow M, Notarangelo L, Grimbacher B, Cunningham-Rundles C, Stein M, Helbert M, Gathmann B, Kindle G, Knight A, Ochs H, Sullivan K, Franco J. Immunodeficiencies. Clin Exp Immunol. 2009; 158 Suppl 1: 14-22. PubMed

Davies G, Thrasher A. Update on the hyper immunoglobulin M syndromes. Br J Haematol. 2010; 149(2): 167-80. PubMed

Freeman A, Holland S. The hyper-IgE syndromes. Immunol Allergy Clin North Am. 2008; 28(2): 277-91, viii. PubMed

Gouilleux-Gruart V, Schleinitz N, Fischer A. Primary immune deficiencies: practical questions. Curr Opin Allergy Clin Immunol. 2013; 13 Suppl 2: S67-78. PubMed

Latiff A, Kerr M. The clinical significance of immunoglobulin A deficiency. Ann Clin Biochem. 2007; 44(Pt 2): 131-9. PubMed

Locke B, Dasu T, Verbsky J. Laboratory diagnosis of primary immunodeficiencies. Clin Rev Allergy Immunol. 2014; 46(2): 154-68. PubMed

Morimoto Y, Routes J. Immunodeficiency overview. Prim Care. 2008; 35(1): 159-73, viii. PubMed

Ochs H, Hagin D. Primary immunodeficiency disorders: general classification, new molecular insights, and practical approach to diagnosis and treatment. Ann Allergy Asthma Immunol. 2014; 112(6): 489-95. PubMed

Ochs H. Patients with abnormal IgM levels: assessment, clinical interpretation, and treatment. Ann Allergy Asthma Immunol. 2008; 100(5): 509-11. PubMed

Slatter M, Gennery A. Clinical immunology review series: an approach to the patient with recurrent infections in childhood. Clin Exp Immunol. 2008; 152(3): 389-96. PubMed

Stiehm R. The four most common pediatric immunodeficiencies. Adv Exp Med Biol. 2007; 601: 15-26. PubMed

van der Hilst J, Frenkel J. Hyperimmunoglobulin D syndrome in childhood. Curr Rheumatol Rep. 2010; 12(2): 101-7. PubMed

Yel L. Selective IgA deficiency. J Clin Immunol. 2010; 30(1): 10-6. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Cronin K, Escobar H, Szekeres K, Reyes-Vargas E, Rockwood A, Lloyd M, Delgado J, Blanck G. Regulation of HLA-DR peptide occupancy by histone deacetylase inhibitors. Hum Vaccin Immunother. 2013; 9(4): 784-9. PubMed

Vaughn C, Baker C, Samowitz W, Swensen J. The frequency of previously undetectable deletions involving 3' Exons of the PMS2 gene. Genes Chromosomes Cancer. 2013; 52(1): 107-12. PubMed

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Last Update: February 2016