eMedicine Specialties > Allergy and Immunology > Immunodeficiencies

Hypogammaglobulinemia: Treatment & Medication

Author: Robert Y Lin, MD, Professor, Department of Medicine, Medical Advisor, Department of Case Management/Utilization Review, New York Medical College; Chief, Allergy and Immunology Section, St Vincent's Catholic Medical Centers, St Vincent's of Manhattan
Coauthor(s): Jenny Shliozberg, MD, Associate Clinical Professor, Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine; Consulting Staff, Department of Pediatrics, Montefiore Hospital Medical Center and Albert Einstein College of Medicine; Director of Pediatric Allergy and Immunization Clinic, Children's Hospital at Montefiore Medical Center; Amit J Shah, MD, Fellow, Division of Allergy and Immunology, Montefiore Medical Center, Albert Einstein College of Medicine
Contributor Information and Disclosures

Updated: Aug 26, 2009

Treatment

Medical Care

  • IgG replacement therapy is the treatment of choice for most primary immunodeficiency syndromes, including X-linked agammaglobulinemia (Bruton disease; XLA), common variable immunodeficiency (CVID), severe combined immunodeficiency (SCID), hyper-IgM, adenosine deaminase (ADA) deficiency, and Wiskott-Aldrich syndrome (WAS). IgG is usually routinely administered intravenously (IVIG) or subcutaneously (SCIG). IgG replacement is usually needed for at least 1 year after hematopoietic stem cell transplantation (HSCT) in patients with SCID.
  • Patients with IgG subclass deficiency should not be given IVIG unless they fail to produce antibodies to protein and polysaccharide antigens and they have significant morbidity due to infection that cannot be managed with antibiotics alone. In selective IgA deficiency, IVIG therapy is not indicated.
  • Effort should be focused on the treatment of infections, allergic reactions, autoimmune diseases, and gastrointestinal diseases. Aggressive and prolonged antibiotic therapy covering S pneumoniae and H influenza is indicated. Because of the high frequency of G lamblia infection in these patients, an empiric course of metronidazole may result in dramatic improvement of the diarrhea and, to a certain extent, of malabsorption syndrome.
  • The treatment of secondary hypogammaglobulinemia is directed at the underlying cause. Successful treatment of nephrotic syndrome and protein-losing enteropathy may result in improvement of Ig levels.
  • IVIG is not indicated for the treatment of lymphoproliferative disorders, unless Ig levels are low in association with recurrent infections or if IVIG is being used for autoimmune conditions such as immune thrombocytopenic purpura (ITP) or immune hemolytic anemia, which may accompany these disorders.
  • Live vaccines (eg, bacille Calmette-Guérin, polio, measles, rubella, mumps) should not be given to patients with T-cell disorders, XLA, or other severe B-cell disorders or to the family members of such patients. In patients with IgA deficiency, live vaccines are not an absolute contraindication if given intramuscularly.
  • High doses of IVIG or intrathecal Ig may be beneficial in patients with XLA who have enteroviral meningoencephalitis.
  • HSCT is the treatment of choice for patients with SCID and, if a matched donor is available, for a patient with ADA deficiency.3
  • In patients with ADA deficiency who lack an HLA-identical sibling, enzyme replacement with polyethylene glycol-ADA (PEG-ADA) may be an effective alternative therapeutic agent.
  • Tumor necrosis factor (TNF) inhibitors have been used to treat granulomatous diseases in patients with CVID.
  • Gene therapy has been shown to be successful in reconstituting immune function in infants with X-linked SCID, but efficacy is less proven in older children and young adults.15 Gene therapy for ADA deficiency is most effective when patients receive myeloablative chemotherapy and are withdrawn from PEG-ADA beforehand. Case series of ADA-deficient patients receiving gene therapy have shown excellent results at 4-year follow-up.16

Activity

Special restrictions on physical activity are not needed.

Medication

The goals of pharmacotherapy are to reduce morbidity and to prevent complications. The standard treatment for hypogammaglobulinemia is IgG replacement, which may be given intravenously or subcutaneously.6,7,17 IgG preparations are approved by the US Food and Drug Administration (FDA) for treatment of primary immunodeficiency disease (primary humoral immunodeficiency) and a few additional indications, but considerable amounts of intravenous immunoglobulins (IVIG) are used "off label" for other conditions.6,17

As reviewed by the American Academy of Allergy, Asthma, and Immunology, the benefit of IgG treatment for these primary immune deficiencies is based on category IIb evidence (13).6 IVIG is approved for only 2 secondary immune deficiencies: B-cell chronic lymphocytic leukemia (B-CLL) and pediatric HIV. The use of IVIG for primary immune defects with normogammaglobulinemia and impaired specific antibody production is based on category III evidence only.6

The usual IVIG dose is 0.4-0.6 g/kg every 3-4 weeks, titrating the dose and interval between infusions to achieve a trough IgG level greater than 500 mg/dL. Usual total monthly doses of subcutaneous IgG (SCIG) are in the same range, given as 100-200 mg/kg/wk. Some practitioners target trough levels 300 mg/dL higher than pretreatment levels, and trough levels >800 mg/dL may improve pulmonary outcomes. Some centers administer a loading dose of 1g/kg if the patient is agammaglobulinemic.6,7,17

Gammaglobulin may also be given intramuscularly or subcutaneously.17 The latter format is useful when allergic reactions limit the dose or rate, but it is becoming increasingly popular even when these problems are not present. SCIG can be given at home by parents or by patients themselves, usually requiring several hours of infusion. Intramuscular gammaglobulin injections were the standard of care before IVIG became readily available and are still useful in certain patients because of the simplicity of administration and fewer reactions. However, local injection site pain can be significant, and the doses that can be given this way are limited.

Up to 44% of patients report adverse reactions to IVIG. These most commonly respond to decreasing the rate of the Ig infusion. Usually, the IVIG-associated reactions are infusion-related and include back pain, abdominal aching, nausea, rhinitis, asthma, chills, low-grade fever, myalgias, and headaches. Renal failure is a less common but serious adverse reaction that was predominately caused by sucrose-containing lyophilized IgG preparations that are no longer available in the United States. Infusion rate reduction, systemic steroids, histamine blockers, and antipyretics or nonsteroidal anti-inflammatory drugs (NSAIDs) can help treat or prevent the reactions.

Although the incidence of reactions is highest during the first infusion, they may occur in repeat infusions of the same product. Although anti-IgA antibodies can be associated with increased reactions, most patients (regardless of anti-IgA antibody status) tolerate IVIG that is not depleted of IgA (low-IgA products should be selected for treatment in patients who cannot tolerate IVIG that is not depleted of IgA). Thrombosis, myocardial infarction, hemolytic anemia, hyperviscosity syndrome, and aseptic meningitis are uncommon but reported adverse events.

Immunoglobulins

Improve clinical and immunologic aspects of the disease.


Immune globulin intravenous (Flebogamma, Gammagard, Gamunex, Octagam, Privigen) and subcutaneous (Vivaglobin)

Results in elevated antiviral or antibacterial antibody titers for 1 mo.
Trough levels >500 mg/dL do not necessarily improve infection control except in certain long-standing infections but may significantly increase cost.

Adult

200-400 mg/kg IV q3-4wk to achieve trough level of >400 mg/dL or 100-200 mg/kg SC qweek

Pediatric

Not established

Globulin preparation may interfere with immune response to live virus vaccine and reduce efficacy (do not administer within 3 mo of vaccination)

Documented hypersensitivity; IgA deficiency

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Check serum IgA before IVIG (when absent, use an IgA-depleted product, eg, Gammagard S/D); infusions may increase serum viscosity and thromboembolic events; may increase risk of migraine attacks, aseptic meningitis (10%), urticaria, pruritus, or petechiae (2-5 d postinfusion to 30 d); increases risk of renal tubular necrosis in elderly patients and in patients with diabetes, volume depletion, and preexisting kidney disease; lab result changes associated with infusions include 6-fold increase in ESR for 2-3 wk and apparent hyponatremia

More on Hypogammaglobulinemia

Overview: Hypogammaglobulinemia
Differential Diagnoses & Workup: Hypogammaglobulinemia
Treatment & Medication: Hypogammaglobulinemia
Follow-up: Hypogammaglobulinemia
References
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References

  1. Sneller MC. Common variable immunodeficiency. Am J Med Sci. Jan 2001;321(1):42-8. [Medline].

  2. Cunningham-Rundles C, Bodian C. Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol. Jul 1999;92(1):34-48. [Medline].

  3. Buckley R. Primary immunodeficiency diseases. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse WW, eds. Allergy: Principles & Practice. 5th ed. Mo: Mosby: St. Louis; 1998:713-34.

  4. Conley ME, Howard V. Clinical findings leading to the diagnosis of X-linked agammaglobulinemia. J Pediatr. Oct 2002;141(4):566-71. [Medline].

  5. Ochs HD, Smith CIE, Puck JM. Primary Immunodeficiency Diseases: A Molecular & Cellular Approach. 2nd ed. USA: Oxford University Press; 2006.

  6. Orange JS, Hossny EM, Weiler CR, et al; Primary Immunodeficiency Committee of the AAAAI. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J Allergy Clin Immunol. Apr 2006;117(4 Suppl):S525-53. [Medline].

  7. Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. 2005;94(5 Suppl 1):S1-63. [Medline].

  8. Chouksey AK, Berger M. Assessment of protein antibody response in patients with suspected immune deficiency. Ann Allergy Asthma Immunol. Feb 2008;100(2):166-8. [Medline].

  9. Paris K, Sorensen RU. Assessment and clinical interpretation of polysaccharide antibody responses. Ann Allergy Asthma Immunol. Nov 2007;99(5):462-4. [Medline].

  10. Buckley R, ed. Immune Deficiency Foundation Diagnostic and Clinical Care Guidelines for Primary Immunodeficiency Diseases, 2nd ed. 2009. Immune Deficiency Foundation. Available at http://www.primaryimmune.org/publications/book_diag/IDFDiagnosticandClinicalCareGuidelines_2ndEdition.pdf. Accessed August 17, 2009.

  11. Boztug K, Dewey RA, Klein C. Development of hematopoietic stem cell gene therapy for Wiskott-Aldrich syndrome. Curr Opin Mol Ther. Oct 2006;8(5):390-5. [Medline].

  12. Raanani P, Gafter-Gvili A, Paul M, Ben-Bassat I, Leibovici L, Shpilberg O. Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis. Leuk Lymphoma. May 2009;50(5):764-72. [Medline].

  13. Mechanic LJ, Dikman S, Cunningham-Rundles C. Granulomatous disease in common variable immunodeficiency. Ann Intern Med. Oct 15 1997;127(8 Pt 1):613-7. [Medline].

  14. Kainulainen L, Varpula M, Liippo K, Svedstrom E, Nikoskelainen J, Ruuskanen O. Pulmonary abnormalities in patients with primary hypogammaglobulinemia. J Allergy Clin Immunol. Nov 1999;104(5):1031-6. [Medline].

  15. Sokolic R, Kesserwan C, Candotti F. Recent advances in gene therapy for severe congenital immunodeficiency diseases. Curr Opin Hematol. Jul 2008;15(4):375-80. [Medline].

  16. Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. Jan 29 2009;360(5):447-58. [Medline].

  17. Berger M. Principles of and advances in immunoglobulin replacement therapy for primary immunodeficiency. Immunol Allergy Clin North Am. May 2008;28(2):413-37, x. [Medline].

  18. Ballow M, O'Neil K. Approach to the patient with recurrent infections. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse WW, eds. Allergy: Principles & Practice. 5th ed. Mo: Mosby: St. Louis; 1998.

  19. Bjoro K, Haaland T, Skaug K. The spectrum of hepatobiliary disease in primary hypogammaglobulinaemia. J Intern Med. May 1999;245(5):517-24. [Medline].

  20. Bonilla FA, Geha RS. Primary immunodeficiency diseases. J Clin Immunol. 2003;111(2 Suppl):S571-81. [Medline].

  21. Bonilla FA, Geha RS. Update of primary immunodeficiency disease. J Clin Immunol. 2006;117(2):S435-41. [Medline].

  22. Carrol WL, Korsmeyer SJ. Immunoglobulins. In: Frank M, Austen K, Claman H, Unanue E, eds. Samter's Immunologic Diseases. 5th ed. Little, Brown and Company: Boston, Mass; 1995:33-51.

  23. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. Apr 28 2000;288(5466):669-72. [Medline].

  24. Cooper N, Davies EG, Thrasher AJ. Repeated courses of rituximab for autoimmune cytopenias may precipitate profound hypogammaglobulinaemia requiring replacement intravenous immunoglobulin. Br J Haematol. Jun 2009;146(1):120-2. [Medline].

  25. Latiff AH, Kerr MA. The clinical significance of immunoglobulin A deficiency. Ann Clin Biochem. Mar 2007;44(Pt 2):131-9. [Medline].

  26. Li James TC. Immunoglobulin structure and function. In: Middleton E Jr, Reed CE, Ellis EF, Adkinson NF Jr, Yunginger JW, Busse WW, eds. Allergy: Principles & Practice. 5th ed. Mo: Mosby: St. Louis; 1998:46-57.

  27. Pasternack M. Approach to the adult with recurrent infections. UpToDate. Available at www.uptodate.com. Accessed October 8, 2007.

  28. Priary Immunodeficiency Resource Center. National Primary Immunodeficiency Resource Center. Available at info4pi.org. Accessed October 8, 2007.

  29. Smith JK, Krishnaswamy GH, Dykes R, Reynolds S, Berk SL. Clinical manifestations of IgE hypogammaglobulinemia. Ann Allergy Asthma Immunol. Mar 1997;78(3):313-8. [Medline].

  30. Stiehm ER. Immunologic Disorders in Infants and Children. 4th ed. WB Saunders Co; 1996.

  31. Tsiodras S, Samonis G, Keating MJ, Kontoyiannis DP. Infection and immunity in chronic lymphocytic leukemia. Mayo Clin Proc. Oct 2000;75(10):1039-54. [Medline].

  32. World Health Organization Scientific Group. Primary immunodeficiency diseases. Report of a WHO scientific group. Clin Exp Immunol. Aug 1997;109 Suppl 1:1-28. [Medline].

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Further Reading

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Keywords

hypogammaglobulinemia, B-cell disorders, T-cell disorders, humoral immunity deficiency, hyper-IgM syndromes, cellular immunity deficiency, antibody deficiency, immunoglobulins, Igs, common variable immunodeficiency, CVID, Bruton's disease, Bruton disease, Hyper-IgM syndromes, intravenous immunoglobulin, IVIG, immunodeficiency, IgG subclass deficiency, subcutaneous IgG, SCIG, Transient Hypogammaglobulinemia of Infancy, X-linked severe combined immunodeficiency, XSCID

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Contributor Information and Disclosures

Author

Robert Y Lin, MD, Professor, Department of Medicine, Medical Advisor, Department of Case Management/Utilization Review, New York Medical College; Chief, Allergy and Immunology Section, St Vincent's Catholic Medical Centers, St Vincent's of Manhattan
Robert Y Lin, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology and American Federation for Medical Research
Disclosure: Nothing to disclose.

Coauthor(s)

Jenny Shliozberg, MD, Associate Clinical Professor, Department of Pediatrics, Division of Allergy and Immunology, Albert Einstein College of Medicine; Consulting Staff, Department of Pediatrics, Montefiore Hospital Medical Center and Albert Einstein College of Medicine; Director of Pediatric Allergy and Immunization Clinic, Children's Hospital at Montefiore Medical Center
Jenny Shliozberg, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American College of Allergy, Asthma and Immunology, and International AIDS Society
Disclosure: Nothing to disclose.

Amit J Shah, MD, Fellow, Division of Allergy and Immunology, Montefiore Medical Center, Albert Einstein College of Medicine
Amit J Shah, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, and American College of Physicians
Disclosure: Nothing to disclose.

Medical Editor

Melvin Berger, MD, PhD, Adjunct Professor of Pediatrics and Pathology, Case Western Reserve University; Senior Medical Director, Clinical Research and Development, CSL Behring, LLC
Melvin Berger, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Clinical Investigation, and Clinical Immunology Society
Disclosure: CSL Behring Salary Employment

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Michael R Simon, MD, MA, Clinical Professor Emeritus, Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine; Adjunct Staff, Division of Allergy and Immunology, Department of Internal Medicine, William Beaumont Hospital
Michael R Simon, MD, MA is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American College of Allergy, Asthma and Immunology, American College of Physicians, American Federation for Medical Research, Michigan Allergy and Asthma Society, Michigan State Medical Society, Royal College of Physicians and Surgeons of Canada, and Society for Experimental Biology and Medicine
Disclosure: Secretory IgA, Inc. Ownership interest Board membership

CME Editor

Timothy D Rice, MD, Associate Professor, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Saint Louis University School of Medicine
Timothy D Rice, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Physicians
Disclosure: Nothing to disclose.

Chief Editor

Michael A Kaliner, MD, Clinical Professor of Medicine, George Washington University School of Medicine; Chief, Section of Allergy and Immunology, Washington Hospital Center; Medical Director, Institute for Asthma and Allergy
Michael A Kaliner, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American Society for Clinical Investigation, American Thoracic Society, and Association of American Physicians
Disclosure: Abbott Consulting fee Consulting; Alcon Consulting fee Consulting; Glaxo Consulting fee Consulting; Greer Consulting fee Consulting; Sanofi Consulting fee Consulting; Schering Consulting fee Consulting; Teva  Consulting; Meda Honoraria Speaking and teaching

 
 
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