eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Delayed-type Hypersensitivity: Follow-up

Author: Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-New Jersey Medical School
Contributor Information and Disclosures

Updated: Jun 2, 2009

Follow-up

Further Inpatient Care

  • Consider patients with most T-cell disorders for stem cell transplantation, usually by bone marrow transplantation using an major histocompatibility complex (MHC)-matched related or unrelated donor.
  • Only a few cases of bone marrow transplantation (BMT) have been reported in patients with mutations in the interferon (IFN)-g and interleukin (IL)-12/IL-23 signaling pathways with rather unfavorable results. Intact T-cell functions other than IFN-g/IL-12/IL-23 axis increases the risk of graft rejection and concurrent atypical mycobacterial infection usually present at the time of BMT may increase the risk of post-BMT complications.9,10

Further Outpatient Care

Inpatient & Outpatient Medications

Deterrence/Prevention

  • Patients in whom cell-mediated immunodeficiency diseases are suspected should never receive the bacille Calmette-Guérin (BCG) or smallpox vaccine. Similarly, the measles, mumps, rubella (MMR) vaccine is contraindicated, although this vaccine is not administered until age 1 year, by which time most T-cell disorders have been diagnosed. Guidelines regarding the administration of the MMR vaccine have been updated.11
  • Patients with IFNGR1, IFNGR2, STAT-1, IL12P40, or IL12RB1 mutations are advised to receive prophylaxis against nontuberculosis mycobacteria (NTM) using rifabutin and clarithromycin.

Complications

  • Antigens that are currently available for delayed-type hypersensitivity (DTH) skin testing are not associated with significant morbidity and do not cause mortality.
  • Experimental animal models of immunodeficiency with absent delayed-type hypersensitivity suggest that other infections may also occur in the absence of effective cell-mediated immunity (CMI). These infections include L monocytogenes, L pneumophila, T gondii, and Leishmania species.
    • In humans with idiopathic disseminated BCG or mutations in the IFN-γ signaling pathway, the risk of contracting nontyphus Salmonella infections increases.
    • One report describes severe infections with viruses (eg, respiratory syncytial virus [RSV], parainfluenza virus, herpes simplex virus (HSV), cytomegalovirus [CMV], and varicella-zoster virus [VZV]) in a patient with an IFN-γ signaling pathway defect.
    • Some patients with IFNGR1 mutations have antibody responses to HSV, CMV, VZV, and Epstein-Barr virus (EBV) without clinical infection, suggesting that their host response to these viruses is intact.

Prognosis

  • Adequate nourishment and discontinuation of drug therapy can reverse anergy caused by malnutrition and immunosuppression by immunomodulating agents, respectively.
  • As noted in Mortality/Morbidity, severe mutations in IFNGR1, IFNGR2, STAT-1, IL12P40, and IL12RB1 lead to lethal disseminated infections with NTM. Mutations in the IFN-g signaling pathway that cause milder clinical infections are described; many of these patients benefit from exogenous IFN-g therapy.

Patient Education

  • Regarding IFNGR1, IFNGR2, STAT-1, IL12P40, and IL12RB1 mutations, inform families about the risks of infection so that appropriate steps to avoid exposure to infection are instituted.
    • Families should be aware that BCG and live viral vaccines are contraindicated.
    • Genetic counseling is an essential part of medical care for the family. Inform parents of the 1 out of 4 risk for affected infants in autosomal recessive gene mutations. Mutations in the intracytoplasmic domain of IFNGR1 result in autosomal dominant transmission.
    • If bone marrow transplantation is considered a therapeutic option, an adequate informed consent consultation for stem cell reconstitution must include the high risk for life-threatening infection during the preparative immunosuppressive regimen in addition to the risk for failure to engraft and graft versus host disease (GVHD). Although successful complete immune reconstitution from bone marrow transplantation can be obtained using fully matched related and unrelated donors, patients may not engraft or may experience GVHD posttransplant. Other forms of stem cell reconstitution that can be offered include cord cell transplantation. Gene therapy is expected to be an option in the future.
  • The Immune Deficiency Foundation is an important resource for education and for support for patients and families with any primary immunodeficiency disease. The current address is 40 W. Chesapeake Ave, Suite 308, Towson, MD 21204. Some states have local chapters.
  • The Jeffrey Modell Foundation at 747 Third Avenue, New York, NY 10017 provides support and raises funds.
  • For excellent patient education resources, visit eMedicine's Allergy Center.

Miscellaneous

Medicolegal Pitfalls

  • Failure to investigate cell-mediated immunity in patients with disseminated bacille Calmette-Guérin (BCG), nontuberculosis mycobacteria (NTM), or unusually severe candidal infections raises the specter of legal liability. Look for a clinical history of consanguinity and other family members with similar clinical infections.
  • Offer mutational analysis for suspected T-cell defects and discuss the opportunity for prenatal diagnosis with the family. Any autosomal recessive mutation places siblings at a 1 out of 4 risk. An autosomal dominant mutation results in a 1 out of 2 risk.

Special Concerns

  • BCG is commonly administered to infants at birth or in the first 3 months of life in some countries but not in the United States; it is contraindicated when T-cell disorders are suspected.
  • Infections with T gondii and Leishmania species and fungal infections, such as coccidioidomycosis and histoplasma, are theoretical risks for patients with primary immunodeficiencies involving the IFN-g/IL-12/IL-23 signaling pathway, including those with IFNGR1, IFNGR2, STAT-1, IL-12P40, and IL12R mutations.
 
Acknowledgments

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author Ann O'Neill Shigeoka, MD, to the original writing and development of this article.



More on Delayed-type Hypersensitivity

Overview: Delayed-type Hypersensitivity
Differential Diagnoses & Workup: Delayed-type Hypersensitivity
Treatment & Medication: Delayed-type Hypersensitivity
Follow-up: Delayed-type Hypersensitivity
References
[ CLOSE WINDOW ]

References

  1. Nakae S, Komiyama Y, Nambu A, et al. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity. Sep 2002;17(3):375-87. [Medline].

  2. Iwakura Y, Nakae S, Saijo S, Ishigame H. The roles of IL-17A in inflammatory immune responses and host defense against pathogens. Immunol Rev. Dec 2008;226:57-79. [Medline].

  3. Takeshita K, Yamasaki T, Akira S, Gantner F, Bacon KB. Essential role of MHC II-independent CD4+ T cells, IL-4 and STAT6 in contact hypersensitivity induced by fluorescein isothiocyanate in the mouse. Int Immunol. May 2004;16(5):685-95. [Medline].

  4. He D, Wu L, Kim HK, Li H, Elmets CA, Xu H. CD8+ IL-17-producing T cells are important in effector functions for the elicitation of contact hypersensitivity responses. J Immunol. Nov 15 2006;177(10):6852-8. [Medline].

  5. Chen J, Liu X. The role of interferon gamma in regulation of CD4+ T-cells and its clinical implications. Cell Immunol. 2009;254(2):85-90. [Medline].

  6. Al-Muhsen S, Casanova JL. The genetic heterogeneity of mendelian susceptibility to mycobacterial diseases. J Allergy Clin Immunol. Dec 2008;122(6):1043-51; quiz 1052-3. [Medline].

  7. Albanesi C, Cavani A, Girolomoni G. IL-17 is produced by nickel-specific T lymphocytes and regulates ICAM-1 expression and chemokine production in human keratinocytes: synergistic or antagonist effects with IFN-gamma and TNF-alpha. J Immunol. Jan 1 1999;162(1):494-502. [Medline].

  8. Milner JD, Brenchley JM, Laurence A, et al. Impaired T(H)17 cell differentiation in subjects with autosomal dominant hyper-IgE syndrome. Nature. Apr 10 2008;452(7188):773-6. [Medline].

  9. Roesler J, Horwitz ME, Picard C, et al. Hematopoietic stem cell transplantation for complete IFN-gamma receptor 1 deficiency: a multi-institutional survey. J Pediatr. Dec 2004;145(6):806-12. [Medline].

  10. Chantrain CF, Bruwier A, Brichard B, et al. Successful hematopoietic stem cell transplantation in a child with active disseminated Mycobacterium fortuitum infection and interferon-gamma receptor 1 deficiency. Bone Marrow Transplant. Jul 2006;38(1):75-6. [Medline].

  11. [Guideline] CDC. Update: recommendations from the Advisory Committee on Immunization Practices (ACIP) regarding administration of combination MMRV vaccine. MMWR Morb Mortal Wkly Rep. Mar 14 2008;57(10):258-60. [Medline].

  12. Altare F, Durandy A, Lammas D, et al. Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency. Science. May 29 1998;280(5368):1432-5. [Medline].

  13. Altare F, Lammas D, Revy P, et al. Inherited interleukin 12 deficiency in a child with bacille Calmette-Guerin and Salmonella enteritidis disseminated infection. J Clin Invest. Dec 15 1998;102(12):2035-40. [Medline].

  14. Askenase PW. Effector and regulatory molecules and mechanisms in delayed type hypersensitivity. In: Middleton E, et al, eds. Allergy: Principles and Practice. Vol 1. 1998:323-41.

  15. Casanova JL, Abel L. The human model: a genetic dissection of immunity to infection in natural conditions. Nat Rev Immunol. Jan 2004;4(1):55-66. [Medline].

  16. Chantrain CF, Bruwier A, Brichard B, et al. Successful hematopoietic stem cell transplantation in a child with active disseminated Mycobacterium fortuitum infection and interferon-gamma receptor 1 deficiency. Bone Marrow Transplant. Jul 2006;38(1):75-6. [Medline].

  17. Chapgier A, Wynn RF, Jouanguy E, et al. Human complete Stat-1 deficiency is associated with defective type I and II IFN responses in vitro but immunity to some low virulence viruses in vivo. J Immunol. Apr 15 2006;176(8):5078-83. [Medline].

  18. de Jong R, Altare F, Haagen IA, et al. Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients. Science. May 29 1998;280(5368):1435-8. [Medline].

  19. Dorman SE, Holland SM. Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection. J Clin Invest. Jun 1 1998;101(11):2364-9. [Medline].

  20. Dorman SE, Picard C, Lammas D, et al. Clinical features of dominant and recessive interferon gamma receptor 1 deficiencies. Lancet. Dec 11-17 2004;364(9451):2113-21. [Medline].

  21. Dorman SE, Uzel G, Roesler J, et al. Viral infections in interferon-gamma receptor deficiency. J Pediatr. Nov 1999;135(5):640-3. [Medline].

  22. Dupuis S, Doffinger R, Picard C, et al. Human interferon-gamma-mediated immunity is a genetically controlled continuous trait that determines the outcome of mycobacterial invasion. Immunol Rev. Dec 2000;178:129-37. [Medline].

  23. Horwitz ME, Uzel G, Linton GF, et al. Persistent Mycobacterium avium infection following nonmyeloablative allogeneic peripheral blood stem cell transplantation for interferon-gamma receptor-1 deficiency. Blood. Oct 1 2003;102(7):2692-4. [Medline].

  24. Huang D, Cancilla MR, Morahan G. Complete primary structure, chromosomal localization, and definition of polymorphisms of the gene encoding the human interleukin-12 p40 subunit. Genes Immun. Dec 2000;1(8):515-20. [Medline].

  25. Jouanguy E, Altare F, Lamhamedi S, et al. Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guerin infection. N Engl J Med. Dec 26 1996;335(26):1956-61. [Medline].

  26. Jouanguy E, Dupuis S, Pallier A, et al. In a novel form of IFN-gamma receptor 1 deficiency, cell surface receptors fail to bind IFN-gamma. J Clin Invest. May 2000;105(10):1429-36. [Medline].

  27. Jouanguy E, Lamhamedi-Cherradi S, Altare F, et al. Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guerin infection and a sibling with clinical tuberculosis. J Clin Invest. Dec 1 1997;100(11):2658-64. [Medline].

  28. Jouanguy E, Lamhamedi-Cherradi S, Lammas D, et al. A human IFNGR1 small deletion hotspot associated with dominant susceptibility to mycobacterial infection. Nat Genet. Apr 1999;21(4):370-8. [Medline].

  29. Lammas DA, De Heer E, Edgar JD, et al. Heterogeneity in the granulomatous response to mycobacterial infection in patients with defined genetic mutations in the interleukin 12-dependent interferon-gamma production pathway. Int J Exp Pathol. Feb 2002;83(1):1-20. [Medline].

  30. Newport MJ, Huxley CM, Huston S, et al. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. Dec 26 1996;335(26):1941-9. [Medline].

  31. Novelli F, Casanova JL. The role of IL-12, IL-23 and IFN-gamma in immunity to viruses. Cytokine Growth Factor Rev. Oct 2004;15(5):367-77. [Medline].

  32. Roesler J, Horwitz ME, Picard C, et al. Hematopoietic stem cell transplantation for complete IFN-gamma receptor 1 deficiency: a multi-institutional survey. J Pediatr. Dec 2004;145(6):806-12. [Medline].

  33. Rosenzweig SD, Holland SM. Congenital defects in the interferon-gamma/interleukin-12 pathway. Curr Opin Pediatr. Feb 2004;16(1):3-8. [Medline].

  34. Rosenzweig SD, Holland SM. Defects in the interferon-gamma and interleukin-12 pathways. Immunol Rev. Feb 2005;203:38-47. [Medline].

  35. Schnorr JJ, Cutts FT, Wheeler JG, et al. Immune modulation after measles vaccination of 6-9 months old Bangladeshi infants. Vaccine. Jan 8 2001;19(11-12):1503-10. [Medline].

  36. Sharma KC, Stevens D, Casey L, Kesten S. Effects of high-dose inhaled fluticasone propionate via spacer on cell-mediated immunity in healthy volunteers. Chest. Oct 2000;118(4):1042-8. [Medline].

  37. Vankayalapati R, Wizel B, Samten B, et al. Cytokine profiles in immunocompetent persons infected with Mycobacterium avium complex. J Infect Dis. Feb 1 2001;183(3):478-84. [Medline].

[ CLOSE WINDOW ]

Further Reading

[ CLOSE WINDOW ]

Keywords

delayed-type hypersensitivity, DTH, DTH reaction, DTH response, delayed-type hypersensitivity reaction, delayed type hypersensitivity, delayed hypersensitivity, hypersensitive response, hypersensitive reaction, cell mediated immunity, CMI, antigen-presenting cells, APCs, cell-mediated immunity to recall antigens, anergy, anergic reaction, T cell, T-cell receptor, Candida antigen, Candida infection, DTH skin test, T-cell disorder, T-cell defect, bone marrow transplantation, BMT
Mycobacterium tuberculosis, tetanus, Candida, Trichophyton, mumps, contact hypersensitivity, nickel, dinitrochlorobenzene, DNCB, picryl chloride, leprosy, poison ivy, Listeria monocytogenes, Legionella pneumophila, Toxoplasma gondii, Leishmania, lymphocytic choriomeningitis virus, mouse hepatitis virus, herpes simplex virus, HSV, malnutrition, atopic dermatitis, MMR vaccine, sarcoidosis, mononucleosis, HIV, influenza, malignant lymphomas, severe combined immunodeficiency, SCID, cytomegalovirus, CMV, Hodgkin lymphoma, asthma, atopy, glomerulonephritis, treatment, diagnosis

[ CLOSE WINDOW ]

Contributor Information and Disclosures

Author

Harumi Jyonouchi, MD, Associate Professor, Division of Pulmonary Allergy/Immunology and Infectious Diseases, Department of Pediatrics, UMDNJ-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.

Medical Editor

Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Terry Chin, MD, PhD 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 College of Chest Physicians, American Thoracic Society, California Thoracic Society, Clinical Immunology Society, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

John Wilson Georgitis, MD, Consulting Staff, Lafayette Allergy Services
John Wilson Georgitis, 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 College of Chest Physicians, American Lung Association, American Medical Writers Association, and American Thoracic Society
Disclosure: Nothing to disclose.

CME Editor

David Pallares, MD, Clinical Assistant Professor, Department of Pediatrics, Division of Allergy and Immunology, University of Louisville
David Pallares, MD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology
Disclosure: Nothing to disclose.

Chief Editor

Russell W Steele, MD, Head, Division of Pediatric Infectious Diseases, Ochsner Children's Health Center; Clinical Professor, Department of Pediatrics, Tulane University School of Medicine
Russell W Steele, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, Infectious Diseases Society of America, Louisiana State Medical Society, Pediatric Infectious Diseases Society, Society for Pediatric Research, and Southern Medical Association
Disclosure: None None None

 
 
HONcode

We subscribe to the
HONcode principles of the
Health On the Net Foundation

All material on this website is protected by copyright, Copyright© 1994- by Medscape.
This website also contains material copyrighted by 3rd parties.

DISCLAIMER: The content of this Website is not influenced by sponsors. The site is designed primarily for use by qualified physicians and other medical professionals. The information contained herein should NOT be used as a substitute for the advice of an appropriately qualified and licensed physician or other health care provider. The information provided here is for educational and informational purposes only. In no way should it be considered as offering medical advice. Please check with a physician if you suspect you are ill.