X-linked Immunodeficiency With Hyper IgM Workup

  • Author: C Lucy Park; Chief Editor: Harumi Jyonouchi, MD   more...
 
Updated: Sep 28, 2010
 

Laboratory Studies

  • Most early descriptions of X-linked immunodeficiency with hyper–immunoglobulin M (XHIGM) reported that patients had elevated serum immunoglobulin (Ig)M levels but markedly reduced IgG, IgA, and IgE levels. According to the US XHIGM Registry report in 2003, elevated IgM levels were found in less than one third of patients.[2] All patients had reduced levels of IgG. More than three fourths of patients had reduced levels of IgA.
  • Diagnosis is confirmed by demonstrating a deficient expression of CD40 ligand on activated CD4+ T lymphocytes using flow cytometric analysis with anti–CD40 ligand monoclonal antibody. Phenotypical analysis of circulating lymphocytes (CD3, CD4, CD8, and CD19 expression) generally shows normal counts of T and B cells. One case report described a man with normal expression of CD40L on activated T cells who was found to have hypomorphic mutations of the CD40L gene.
  • Diagnostic criteria used for the US XHIGM Registry consisted of 2 of the following: (1) mutation of CD40L, (2) a positive family history of a lateral male relative with the HIGM syndrome, and (3) defective expression of CD40 ligand on activated T lymphocytes. Patients with reduced CD40L expression only, without positive family history or mutation of CD40L, cannot be included because this reduced expression can occur in some patients with common variable immunodeficiency (CVID).
  • Functional antibody production that requires T-cell and B-cell interaction (T-cell dependent) is markedly impaired. Antibodies against T-cell–dependent antigens, such as antibodies to tetanus-toxoid, diphtheria-toxoid, and protein-conjugated H influenzae type b antigens, are absent. Although pneumococcal polysaccharide antigens are T-cell independent, IgG antibodies against these antigens are not produced. Antibodies to T-cell–independent antigens in the IgM class, such as isohemagglutinin (antibodies against ABO blood group antigens), are often normal.
  • Despite decreased or absent functional antibody production, these patients may produce a large amount of autoantibodies against erythrocytes, platelets, and other organs, such as antiparietal cells and antithyroid microsomal autoantibodies.
  • In vitro lymphocyte stimulation with T-cell mitogens (phytohemagglutinin or concanavalin A) was normal in over 90% of patients with XHIGM. A minority of patients had a reduced in vitro proliferative response to tetanus toxoid.
  • B cells from patients with XHIGM can be driven to secrete immunoglobulins of various isotypes in the presence of pokeweed mitogens when cocultured with helper T lymphoblasts from a patient with a Sézary-like syndrome. This finding illustrates a primary T-cell defect in XHIGM.
  • Neutropenia frequently accompanies XHIGM and can be chronic, cyclic, or occasional. Bone marrow studies show maturation arrest of the myeloid lineage at the promyelocyte-myelocyte stage. Autoantibodies to neutrophils are not detected.
  • Evaluation of infection by appropriate culture and determination of antibiotic sensitivities are integral to managing any immune deficiency disease. Sputum and stool cultures are commonly needed, and obtaining a culture at any acute infection site before administering antibiotics is crucial.
  • Perform liver function tests at diagnosis and yearly thereafter because subclinical hepatitis is not uncommon. Viral hepatitis (B and C) testing requires antigen detection because most patients are unable to produce antibodies. Perform biopsies on patients with hepatic disease to best delineate the extent of disease.
  • Gene mutation analysis should be performed for the final confirmation of diagnosis. If the precise mutation in CD40L is known in a given family, and if the fetus is male, a prenatal diagnosis is possible. Women in the family can be tested to see if they carry the mutation and are, therefore, at risk for having an affected son.
  • About 20% of patients with XHIGM express nonfunctional CD40 ligand on T cells that can bind anti–CD40 ligand monoclonal antibodies. Therefore, these patients may require testing to determine whether their T cells can bind to CD40 molecules using CD40-Ig fusion protein. The final molecular diagnosis may depend on sequence analysis of CD40L using cDNA or genomic DNA.
  • A physician consultation service is available through the Immune Deficiency Foundation.
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Imaging Studies

  • Chest radiographs and sinus radiographs or CT scans are initially needed for baseline studies. Patients with chronic sinopulmonary disease are customarily reevaluated at intervals with CT imaging.
  • Abdominal CT imaging or MRI is indicated in patients with hepatomegaly, cholangitis, or abnormal liver function test findings.
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Other Tests

  • Pulmonary function tests are essential at diagnosis and yearly thereafter to monitor for chronic lung disease. Approximately one fourth of patients with XHIGM have bronchiectasis; the risk of bronchiectasis is higher if the initiation of intravenous immunoglobulin (IVIG) therapy is delayed.
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Procedures

  • Bronchoscopy and bronchoalveolar lavage may be required in patients with severe pulmonary disease that does not respond to usual antibiotic therapy or patients who may have P carinii pneumonia (PCP) in order to obtain a specimen for identification of pathogens.
  • Patients with chronic diarrhea may require endoscopy and biopsy to rule out inflammatory bowel disease.
  • Patients with abnormal liver function may require percutaneous liver biopsy.
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Histologic Findings

  • Lymph node biopsy findings reveal a lack of germinal centers, attributed to ineffective CD40L-CD40 interaction in the extrafollicular areas, resulting in poor recruitment of germinal center precursors.
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Contributor Information and Disclosures
Author

C Lucy Park  MD, Head, Division of Allergy, Immunology, and Pulmonology, Associate Professor, Department of Pediatrics, University of Illinois at Chicago College of Medicine

C Lucy Park is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Medical Association, Chicago Medical Society, Clinical Immunology Society, and Illinois State Medical Society

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; Professor, Department of Quantitative Methods, University of Medicine and Dentistry of New Jersey

James M Oleske 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.

David J Valacer, MD  Consulting Staff, Hoffman La Roche Pharmaceuticals

David J Valacer, 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 Thoracic Society, and New York Academy of Sciences

Disclosure: Nothing to disclose.

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

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, University of Medicine and Dentistry of New Jersey-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.

References

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  2. Winkelstein JA, Marino MC, Ochs H, et al. The X-linked hyper-IgM syndrome: clinical and immunologic features of 79 patients. Medicine (Baltimore). Nov 2003;82(6):373-84. [Medline].

  3. Matamoros Flori N, Mila Llambi J, Espanol Boren T, et al. Primary immunodeficiency syndrome in Spain: first report of the National Registry in Children and Adults. J Clin Immunol. Jul 1997;17(4):333-9. [Medline].

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  16. Durandy A, Schiff C, Bonnefoy JY, et al. Induction by anti-CD40 antibody or soluble CD40 ligand and cytokines of IgG, IgA and IgE production by B cells from patients with X-linked hyper IgM syndrome. Eur J Immunol. Sep 1993;23(9):2294-9. [Medline].

  17. Durandy A, Taubenheim N, Peron S, Fischer A. Pathophysiology of B-cell intrinsic immunoglobulin class switch recombination deficiencies. Adv Immunol. 2007;94:275-306. [Medline].

  18. Eijkhout HW, van Der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. Aug 7 2001;135(3):165-74. [Medline]. [Full Text].

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  21. Hollenbaugh D, Wu LH, Ochs HD, et al. The random inactivation of the X chromosome carrying the defective gene responsible for X-linked hyper IgM syndrome (X-HIM) in female carriers of HIGM1. J Clin Invest. Aug 1994;94(2):616-22. [Medline]. [Full Text].

  22. Lin Q, Rohrer J, Allen RC, Larché M, Greene JM, Shigeoka AO, et al. A single strand conformation polymorphism study of CD40 ligand. Efficient mutation analysis and carrier detection for X-linked hyper IgM syndrome. J Clin Invest. Jan 1 1996;97(1):196-201. [Medline]. [Full Text].

  23. Ochs HD. Patients with abnormal IgM levels: assessment, clinical interpretation, and treatment. Ann Allergy Asthma Immunol. May 2008;100(5):509-11. [Medline].

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This infant with X-linked immunodeficiency with hyper-immunoglobulin M (XHIGM) developed severe diarrhea and hypoproteinemia and presented to a clinic with high fever. Blood culture grew Pseudomonas aeruginosa. Marked leukocytosis was present. The WBC count was 26,000/mL, with 67% neutrophils. Stool culture and examination findings were negative for cryptosporidia, Giardia species, bacteria, or viruses.
During the primary antibody response, B cells in the bone marrow produce immunoglobulin M (IgM) and immunoglobulin D (IgD) antibodies of low avidity. This process occurs largely in an antigen-independent way (pro-B cells, pre-B cells). Once IgM B cells are engaged with antigens, B cells start the secondary antibody repertoire generation by undergoing 2 genetic alterations; class-switch recombination (switching from IgM to IgG, IgA, or IgE) and somatic hypermutation (introduction of point mutations in the V regions of the Ig genes, the antigen-biding sites, resulting in an expansion of the antibody repertoire to generate high-affinity antigen-specific antibodies). The secondary antibody repertoire generation is antigen and T-cell dependent and occurs in peripheral lymphoid organs, mainly through the interaction between CD40L (CD154) expressed on activated CD4+ T cells and CD40 expressed on B cells.
Table 1. Clinical and Immunologic Features of Hyper-IgM Syndromes[8]
XHIGMCD40 defectEDA-IDAR-AIDAID- CterAID-Δ CUNG defectCSR defect- upstream from DNA cleavageCSR defect-downstream from DNA cleavage
DefectCD40LCD40NEMOAIDAIDAIDUNGUnknownUnknown
InheritanceXLARXLARARADARARAR
Lymphadenopathy---+++++++++
Opportunistic Infection++-------
Autoimmunity±±++++--+
Serum IgMN or ↑ N or ↑ N or ↑ ↑ ↑ ↑ ↑ ↑↑ ↑ N or ↑ N or ↑
CD40-induced CSRNUDVariableUDUDUDUDUDUD
SHM↓↓Variable↓ ↓ NNN but biasedNN
Table 2. Immune Globulin, Intravenous[9, 10, 11, 12]
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



(CSL Behring)



Kistler-Nitschmann fractionation; pH 4 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
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 incubation4.8-5.1Contains sorbitol (40 mg/mL); do not administer if fructose intolerantReady-for-use liquid 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 4.0 incubation, trace pepsin, nanofiltration6.6Per gram of IgG: 1.67 g sucrose, < 20 mg NaClLyophilized powder 3%, 6%, 9%, 12%720
Privigen Liquid 10%



(CSL Behring)



Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration4.6-5L-proline (approximately 250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers (eg, sucrose, maltose) Ready-for use liquid 10%< 25
Table 3. Subcutaneous Immune Globulin
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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