X-linked Immunodeficiency With Hyper IgM Follow-up

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

Further Inpatient Care

  • Inpatient care may be necessary for any serious clinical conditions associated with X-linked immunodeficiency with hyper–immunoglobulin M (XHIGM). Hospitalization due to severe infection is uncommon once intravenous immunoglobulin (IVIG) therapy is started. IVIG can be administered in outpatient clinics or at home to minimize interruptions of normal living.
  • Bone marrow transplantation (BMT) may be considered in young patients without bronchiectasis or severe chronic infections who have an human leukocyte antigen (HLA)-matched sibling donor. Cord blood stem cells (fully or partially matched) or bone marrow from an unrelated matched donor may be considered if a matched sibling donor is not available.
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Further Outpatient Care

  • Monitor patients who are stable every 2-3 months. More frequent observation is appropriate for patients with intercurrent infection or complications such as autoimmune disorders or viral hepatitis.
  • Empirical antibiotic therapy should be avoided as much as possible. Make every effort to obtain samples for pathogen identification and use specific antimicrobial agents.
  • P carinii (PCP) prophylaxis should be started as soon as diagnosis is established.
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Inpatient & Outpatient Medications

  • See Medical Care.
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Transfer

  • Patients should be transferred to a tertiary care medical facility where experienced clinical immunologists are available for close follow-up.
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Deterrence/Prevention

  • PCP prophylaxis using antibiotics such as trimethoprim-sulfamethoxazole must be started as soon as the diagnosis is established.
  • Patients with XHIGM should not receive live virus vaccines (eg, mumps-measles-rubella [MMR], varicella, or oral polio vaccine) because, although the possibility is remote, the patient may develop infection with the vaccine-strain viruses.
  • Because exposure to Cryptosporidium may cause severe GI symptoms and chronic liver disease, reducing the possibility of drinking contaminated water is important. The family should contact the local water supplier and ask if the water is tested for Cryptosporidium.
  • Prenatal diagnosis is possible once the gene mutation of the index case is identified. Polymerase chain reaction–single strand conformational polymorphism (PCR-SSCP) screening of genomic DNA may be used to make prenatal diagnosis. Because patients with XHIGM develop infections, including life-threatening PCP, in the first few years of life, early institution of IVIG and PCP prophylaxis significantly reduces morbidity and mortality.
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Complications

  • Bronchiectasis is common in patients who experience recurrent episodes of pneumonia. Bacterial pneumonia is mostly preventable using regular IVIG replacement therapy.
  • Liver cirrhosis secondary to hepatitis and cholangitis and eventual liver failure may be fatal. Adenocarcinomas of the liver, biliary tract, and other parts of the GI system are another complication of chronic GI disease.
  • Progressive meningoencephalitis due to enteroviruses has been reported. Degenerative encephalopathy without identifiable infectious etiology has been described. Unfortunately, even very high doses of IVIG did not prevent progression of neurological deterioration.
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Prognosis

  • Prognosis is guarded, even with aggressive IVIG therapy and PCP prophylaxis.
  • A retrospective study by the Registry of the European Society for Immune Deficiency of 56 affected males revealed a 20% survival rate in persons aged 25 years or older. The US XHIGM Registry reported that 11 of 61 surviving patients were aged 20 years or older.
  • A number of patients received BMT or cord blood stem cell transplantation, with variable outcomes. Better outcomes are associated with BMT from an HLA-matched sibling. Successful treatment of a patient with XHIGM using liver transplantation followed by BMT from an HLA-matched, unrelated donor has been reported.
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Patient Education

  • Some US states have local chapters of Immune Deficiency Foundation. The Immune Deficiency Foundation
  • 25 W Chesapeake Ave, Suite 206
  • Towson, MD 21204
  • Consultation calls: 1-877-666-0866
  • The Jeffrey Modell Foundation also provides educational support and raises funds for research. The Jeffrey Modell Foundation
  • 747 3rd Avenue
  • New York, NY 10017
  • Phone: 1-800-JEFF-844
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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].

  4. Levy J, Espanol-Boren T, Thomas C, et al. Clinical spectrum of X-linked hyper-IgM syndrome. J Pediatr. Jul 1997;131(1 Pt 1):47-54. [Medline].

  5. Aschermann Z, Gomori E, Kovacs GG, et al. X-linked hyper-IgM syndrome associated with a rapid course of multifocal leukoencephalopathy. Arch Neurol. Feb 2007;64(2):273-6. [Medline].

  6. Lopez-Granados E, Temmerman ST, Wu L, et al. Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis. Proc Natl Acad Sci U S A. Mar 20 2007;104(12):5056-61. [Medline].

  7. Van Hoeyveld E, Zhang PX, De Boeck K, Fuleihan R, Bossuyt X. Hyper-immunoglobulin M syndrome caused by a mutation in the promotor for CD40L. Immunology. Apr 2007;120(4):497-501. [Medline].

  8. Notarangelo LD, Lanzi G, Peron S, Durandy A. Defects of class-switch recombination. J Allergy Clin Immunol. Apr 2006;117(4):855-64. [Medline].

  9. Garcia-Lloret M, McGhee S, Chatila TA. Immunoglobulin replacement therapy in children. Immunol Allergy Clin North Am. Nov 2008;28(4):833-49, ix. [Medline].

  10. Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations. Immunol Allergy Clin North Am. Nov 2008;28(4):765-78, viii. [Medline].

  11. Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. Aug 15 2005;62(16 Suppl 3):S5-11. [Medline].

  12. Siegel J. The product: all intravenous immunoglobuins are not equivalent. Pharmacotherapy. 2005;25(11 Pt 2):78S-84S.

  13. Cunningham CK, Bonville CA, Ochs HD, et al. Enteroviral meningoencephalitis as a complication of X-linked hyper IgM syndrome. J Pediatr. May 1999;134(5):584-8. [Medline].

  14. Delves PJ, Roitt IM. The immune system. Second of two parts. N Engl J Med. Jul 13 2000;343(2):108-17. [Medline].

  15. Durandy A, Peron S, Fischer A. Hyper-IgM syndromes. Curr Opin Rheumatol. Jul 2006;18(4):369-76. [Medline].

  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].

  19. Etzioni A, Ochs HD. The hyper IgM syndrome--an evolving story. Pediatr Res. Oct 2004;56(4):519-25. [Medline].

  20. Herve M, Isnardi I, Ng YS, et al. CD40 ligand and MHC class II expression are essential for human peripheral B cell tolerance. J Exp Med. Jul 9 2007;204(7):1583-93. [Medline].

  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].

  24. Ochs HD, Winkelstein J. Disorders of the B-cell system. In: Immunologic Disorders in Infants and Children. 4th ed. Philadelphia, PA: WB Saunders; 1996:311-4.

  25. Ramesh N, Geha RS, Notarangelo LD. CD40 ligand and the hyper-IgM syndrome. In: Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. Oxford University Press; 1999:233-49.

  26. Razanajaona D, van Kooten C, Lebecque S, et al. Somatic mutations in human Ig variable genes correlate with a partially functional CD40-ligand in the X-linked hyper-IgM syndrome. J Immunol. Aug 15 1996;157(4):1492-8. [Medline].

  27. Revy P, Muto T, Levy Y, et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell. Sep 1 2000;102(5):565-75. [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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