Close
New

Medscape is available in 5 Language Editions – Choose your Edition here.

 

Combined B-Cell and T-Cell Disorders Treatment & Management

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

Medical Care

Patients with combined immunodeficiencies, such as SCID, XHM, Good syndrome, and WAS, may benefit from intravenous immunoglobulin (IVIG) replacement therapy. Appropriate supportive care, such as early identification of opportunistic infections or nutritional support, are necessary.

  • In WAS, other than prophylactic antibiotics and IVIG, splenectomy for thrombocytopenia and platelet transfusion in acute life-threatening bleeding can be used.
  • NOTE: Do not immunize these patients with live attenuated vaccines.
  • Focus efforts on the treatment of infections, allergic reactions, and autoimmune and gastrointestinal diseases. Aggressive and prolonged antibiotic therapy covering Streptococcus pneumoniae and Haemophilus influenzae is indicated. Prophylactic antibiotic therapy has been recommended for patients with frequent infections. A course of metronidazole may result in dramatic improvement of the patients' diarrhea and, to a certain extent, of malabsorption syndrome. Prophylactic antibiotic therapy may significantly decrease the incidence of infections.
  • Patients with ADA deficiency may benefit from substitution with pegademase bovine ADA. The maximum effect on immunologic function does not occur for several months. (see the package insert for details.)
  • Inherited and acquired diseases of the hematopoietic system can be cured by allogeneic hematopoietic stem cell transplantation. This treatment strategy is highly successful when a human leukocyte antigen (HLA)-matched sibling donor is available; if such a donor is not available, however, few therapeutic options exist. Gene-modified, autologous bone marrow transplantation can circumvent the severe immunologic complications that occur when a related HLA-mismatched donor is used and thus represents an attractive alternative (see below). Bone marrow transplantation or hematopoietic stem cell transplantation (HSCT) may be helpful for patients with SCID. Survival rates in these previously fatal conditions are around 90% in some case series.
    • The discovery of the HLA system in 1968 led to successful bone marrow transplantations. Patients with immunodeficiency syndromes were the first to benefit from this novel therapy.
    • Allogeneic bone marrow transplantation has become the standard of care for certain patients with SCIDs (eg, XSCID, ADA deficiency). Patients with other immunodeficiency syndromes may benefit from bone marrow transplantation or HSCT, including those with WAS or XHM.
      • There are many groups that are exploring the potential benefits of HSCT based on alternative donors. There are several advantages of umbilical cord blood stem cell transplantation (UCBSCT), which include ready availability of the unit, a lower risk of transmitting viral diseases, no risk to the donor, and a lower risk of GVHD even in the absence of a perfect HLA match.
      • Another possibility for patients without a suitable sibling donor is a matched unrelated donor (MUD) HSCT. But in clinical practice, this therapy is limited due to high rates of GVHD and transplant-related mortality.
      • To facilitate the identification of a suitable MUD, there have been recent advances, including the following: (1) the continuous growth of volunteer donors worldwide; (2) high-resolution molecular techniques for HLA typing, which permits a better selection of donors; and (3) advances in critical care that have resulted in a significant decrease in MUD-HSCT transplant related mortality and an increase in the survival of SCID infants who are severely infected at the time of diagnosis.
      • Early diagnosis before the development of permanent lung and liver damage and referral to a specialized center for bone marrow transplantation/HSCT are essential for therapeutic success.
      • Bertrand et al reported on a European experience with 178 patients in 18 centers who were treated with HLA, nonidentical, T-cell–depleted bone marrow transplantation.[16] With a median follow-up of 57 months, disease-free survival was shown to be significantly better for patients with B-positive SCID (60%) than for patients with B-negative SCID (35%).[16]
      • Buckley et al found that the survival rate was not affected by the genetic type, but it was affected by race (ie, more white patients than black or Hispanic patients survived [P < 0.001]) and sex (all girls survived [P = 0.047]).[17]
      • Another report noted the inefficacy of bone marrow transplantation in correcting Job syndrome.[18]
    • Despite the success that has been seen in some SCID patients treated with bone marrow transplantation, in some cases, failure to restore B-cell function or failure or rejection of the graft over time occurrence. A novel alternative strategy to circumvent graft failure/rejection is the use of gene transfer into autologous stem cells using retroviruses.
      • Gene therapy is a viable therapeutic option; advances in biotechnology have enabled the performance of this highly complex treatment for several immunodeficiency syndromes.
      • Cavazzana-Calvo et al published reports of the successful results of gene therapy for SCID-X1 disease in 2 children, opening new horizons for the future of these patients.[3] This therapy resulted in complete immune reconstitution of the lymphoid system, with T-, B-, and NK-cell counts comparable to age-matched controls.[3] An update on these 2 patients by the same authors and a report on 3 others confirmed the previous results.
      • Patients with ADA deficiency were the first to be enrolled in gene therapy trials. Until recently, no successful sustained expression of ADA occurred in treated patients. A trial conducted by Kohn et al is under way.[19]
      • Novel forms of gene therapy are being tested in clinical studies.[5, 20] One approach known as gene-modified autologous HSCT has shown some promising results; this therapy has the potential to circumvent the significant limitations of allogeneic bone marrow transplantation and gene therapy by using postthymic differentiated cells.
      • RNA viruses are the most commonly used vectors to introduce genetic information into hematopoietic stem cells and/or progenitor cells. There have been reports of spontaneous, partial corrections of the phenotype of severe T-cell immunodeficiencies (eg, ADA deficiency, SCID-X1, WAS, RAG1 deficiency, CD3 deficiency) within the past decade. It has been demonstrated that several T-cell precursors which carry a wild-type sequence of the disease-causing gene or mutation with less harmful effects can mature into functional mature T cells that provide adequate immunity. The selective advantage conferred by the expression of either gamma C or ADA in lymphocyte progenitors was confirmed in 3 gene therapy clinical trials.
      • It is striking to note that gene therapy for ADA deficiency was only successful in patients who did not concomitantly receive polyethylene glycol–ADA (PEG-ADA) enzymatic substitution.[21]
Next

Consultations

Consultations should be obtained with specialists from the following specialties:

  • Bone marrow transplantation
  • Gastroenterology
  • Nutrition
  • Infectious diseases
Previous
Next

Diet

In view of the presence of chronic diarrhea, patients often require enteral or parenteral supplementation.

Previous
Next

Activity

Physical activity should be encouraged. Patients may need isolation to decrease the risk of common viral and bacterial infections, such as avoiding crowded places. Strict hygienic practices are important.

Previous
 
 
Contributor Information and Disclosures
Author

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.

Coauthor(s)

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.

Acknowledgements

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.

References
  1. Cavazzana-Calvo M, Fischer A. Gene therapy for severe combined immunodeficiency: are we there yet?. J Clin Invest. 2007 Jun. 117(6):1456-65. [Medline]. [Full Text].

  2. Khiong K, Murakami M, Kitabayashi C, et al. Homeostatically proliferating CD4 T cells are involved in the pathogenesis of an Omenn syndrome murine model. J Clin Invest. 2007 May. 117(5):1270-81. [Medline]. [Full Text].

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

  4. Sinha S, Schwartz RA. Severe combined immunodeficiency. Medscape Reference. Updated August 21, 2006. [Full Text].

  5. Bonilla FA, Geha RS. 2. Update on primary immunodeficiency diseases. J Allergy Clin Immunol. 2006 Feb. 117(2 suppl mini-primer):S435-41. [Medline].

  6. Cachafeiro T, Escobar G, Bakos L, Bakos R. Chronic cutaneous cytomegalovirus infection in a patient with severe combined immunodeficiency syndrome. Br J Dermatol. 2013 Sep 6. [Medline].

  7. Bacalhau S, Freitas C, Valente R, Barata D, Neves C, Schäfer K, et al. Successful Handling of Disseminated BCG Disease in a Child with Severe Combined Immunodeficiency. Case Report Med. 2011. 2011:527569. [Medline]. [Full Text].

  8. Verbsky JW, Baker MW, Grossman WJ, Hintermeyer M, Dasu T, Bonacci B, et al. Newborn Screening for Severe Combined Immunodeficiency; The Wisconsin Experience (2008-2011). J Clin Immunol. 2011 Nov 10. [Medline].

  9. Somech R, Lev A, Simon AJ, Korn D, Garty BZ, Amariglio N, et al. Newborn screening for severe T and B cell immunodeficiency in Israel: a pilot study. Isr Med Assoc J. 2013 Aug. 15(8):404-9. [Medline].

  10. Kelly BT, Tam JS, Verbsky JW, Routes JM. Screening for severe combined immunodeficiency in neonates. Clin Epidemiol. 2013 Sep 16. 5:363-369. [Medline]. [Full Text].

  11. Rozmus J, Junker A, Thibodeau ML, Grenier D, Turvey SE, Yacoub W, et al. Severe Combined Immunodeficiency (SCID) in Canadian Children: A National Surveillance Study. J Clin Immunol. 2013 Oct 12. [Medline].

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

  13. Zhang C, Zhang ZY, Wu JF, Tang XM, Yang XQ, Jiang LP, et al. Clinical characteristics and mutation analysis of X-linked severe combined immunodeficiency in China. World J Pediatr. 2011 Nov 21. [Medline].

  14. Ridanpaa M, van Eenennaam H, Pelin K, et al. Mutations in the RNA component of RNase MRP cause a pleiotropic human disease, cartilage-hair hypoplasia. Cell. 2001 Jan 26. 104(2):195-203. [Medline]. [Full Text].

  15. Chin T, Alonazi N. B-cell and T-cell combined disorders. Medscape Reference. Updated April 5, 2007. [Full Text].

  16. Bertrand Y, Landais P, Friedrich W, et al. Influence of severe combined immunodeficiency phenotype on the outcome of HLA non-identical, T-cell-depleted bone marrow transplantation: a retrospective European survey from the European Group for Bone Marrow Transplantation and the European Society for Immunodeficiency. J Pediatr. 1999 Jun. 134(6):740-8. [Medline].

  17. Buckley RH, Schiff SE, Schiff RI, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 1999 Feb 18. 340(7):508-16. [Medline]. [Full Text].

  18. Gennery AR, Flood TJ, Abinun M, Cant AJ. Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplant. 2000 Jun. 25(12):1303-5. [Medline].

  19. Kohn DB. Adenosine deaminase gene therapy protocol revisited. Mol Ther. 2002 Feb. 5(2):96-7. [Medline]. [Full Text].

  20. Casanova JL, Abel L. Primary immunodeficiencies: a field in its infancy. Science. 2007 Aug 3. 317(5838):617-9. [Medline].

  21. Husain M, Grunebaum E, Naqvi A, et al. Burkitt's lymphoma in a patient with adenosine deaminase deficiency-severe combined immunodeficiency treated with polyethylene glycol-adenosine deaminase. J Pediatr. 2007 Jul. 151(1):93-5. [Medline].

  22. Atluri S, Neville K, Davis M, et al. Epstein-Barr-associated leiomyomatosis and T-cell chimerism after haploidentical bone marrow transplantation for severe combined immunodeficiency disease. J Pediatr Hematol Oncol. 2007 Mar. 29(3):166-72. [Medline].

  23. Chapel H, Puel A, von Bernuth H, Picard C, Casanova JL. Shigella sonnei meningitis due to interleukin-1 receptor-associated kinase-4 deficiency: first association with a primary immune deficiency. Clin Infect Dis. 2005 May 1. 40(9):1227-31. [Medline]. [Full Text].

  24. Chun HJ, Zheng L, Ahmad M, et al. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002 Sep 26. 419(6905):395-9. [Medline].

  25. Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999 Dec. 93(3):190-7. [Medline].

  26. Cooper MD, Lanier LL, Conley ME, Puck JM. Immunodeficiency disorders. Hematology Am Soc Hematol Educ Program. 2003. 314-30. [Medline]. [Full Text].

  27. Creagh EM, Conroy H, Martin SJ. Caspase-activation pathways in apoptosis and immunity. Immunol Rev. 2003 Jun. 193:10-21. [Medline].

  28. Fischer A, Le Deist F, Hacein-Bey-Abina S, et al. Severe combined immunodeficiency. A model disease for molecular immunology and therapy. Immunol Rev. 2005 Feb. 203:98-109. [Medline].

  29. Gennery AR, Cant AJ. Diagnosis of severe combined immunodeficiency. J Clin Pathol. 2001 Mar. 54(3):191-5. [Medline]. [Full Text].

  30. Hadzic N, Pagliuca A, Rela M, et al. Correction of the hyper-IgM syndrome after liver and bone marrow transplantation. N Engl J Med. 2000 Feb 3. 342(5):320-4. [Medline]. [Full Text].

  31. Hermanns P, Bertuch AA, Bertin TK, et al. Consequences of mutations in the non-coding RMRP RNA in cartilage-hair hypoplasia. Hum Mol Genet. 2005 Dec 1. 14(23):3723-40. [Medline]. [Full Text].

  32. Kohn DB. Gene therapy for genetic haematological disorders and immunodeficiencies. J Intern Med. 2001 Apr. 249(4):379-90. [Medline]. [Full Text].

  33. Kuska B. Wiskott-Aldrich syndrome: molecular pieces slide into place. J Natl Cancer Inst. 2000 Jan 5. 92(1):9-11. [Medline]. [Full Text].

  34. Notarangelo LD, Forino C, Mazzolari E. Stem cell transplantation in primary immunodeficiencies. Curr Opin Allergy Clin Immunol. 2006 Dec. 6(6):443-8. [Medline].

  35. Revy P, Malivert L, de Villartay JP. Cernunnos-XLF, a recently identified non-homologous end-joining factor required for the development of the immune system. Curr Opin Allergy Clin Immunol. 2006 Dec. 6(6):416-20. [Medline].

  36. Torgerson TR, Ochs HD. Regulatory T cells in primary immunodeficiency diseases. Curr Opin Allergy Clin Immunol. 2007 Dec. 7(6):515-21. [Medline].

  37. Zhu Q, Watanabe C, Liu T, et al. Wiskott-Aldrich syndrome/X-linked thrombocytopenia: WASP gene mutations, protein expression, and phenotype. Blood. 1997 Oct 1. 90(7):2680-9. [Medline]. [Full Text].

Previous
Next
 
Table 1. Classification of SCID
PathophysiologyCells AffectedInheritanceGenes Involved
Premature cell deathT, B, NKARADA
Defective cytokine–dependent survival signalingT, NKAR



γ c type-XL



JAK3, IL7RA (T cells only), γ c
Defective V(D)J rearrangementT, BARRAG1, RAG2, Artemis
Defective pre-TCR and TCR signalingTARCD3 δ, CD3 ζ, CD3 ε,



CD45



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.
Previous
Next
 
 
 
 
 
All material on this website is protected by copyright, Copyright © 1994-2016 by WebMD LLC. This website also contains material copyrighted by 3rd parties.