eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Delayed-type Hypersensitivity: Differential Diagnoses & Workup

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

Differential Diagnoses

B-Cell and T-Cell Combined Disorders
Measles
Chromosomal Breakage Syndromes
Severe Combined Immunodeficiency
DiGeorge Syndrome
Tuberculosis
Hodgkin Disease
Wiskott-Aldrich Syndrome
Human Immunodeficiency Virus Infection

Other Problems to Be Considered

Consider primary T-cell immunodeficiency, including severe combined immunodeficiency (SCID), when anergy is present. Other well-recognized primary immunodeficiency diseases with anergy include Wiskott-Aldrich syndrome, DiGeorge syndrome, ataxia telangiectasia, and other chromosomal breakage disorders.

Exclude malnutrition and immunosuppression with corticosteroids and other drugs. Certain malignancies, such as Hodgkin disease, are associated with anergy. Consider rheumatologic disease, especially systemic lupus erythematosus as a cause of anergy in specific clinical situations.

Mutations that effect responses to interferon (IFN)-g or its production include IFNGR1, IFNGR2, STAT-1, IL12P4, and IL12RB1. As a result, these patients may manifest altered (often excessive) delayed-type hypersensitivity (DTH) skin test reactivity.

In patients with STAT3 mutations, as seen in patients with autosomal dominant hyper immunoglobulin E (IgE) syndrome, delayed-type hypersensitivity responses may be attenuated due to impaired Th17 cell development.

Workup

Laboratory Studies

  • Characteristics of the antigens determine the delayed-type hypersensitivity (DTH) skin test reactivity. Conjugation of the antigen to lipids facilitates the delayed-type hypersensitivity reaction. This explains the consistent response to mycobacteria in which antigens are isolated from the lipid cell wall. Size, valence, chemical composition, and dose are additional factors that are relevant to immunogenicity. Repetitive testing with the same antigen can cause an immediate immunoglobulin E (IgE)-mediated response and may diminish the delayed-type hypersensitivity skin test reactivity. High doses of antigens that induce predominant Th2 responses, such as in miliary tuberculosis, abrogate the delayed-type hypersensitivity responses by a negative feedback mechanism that suppresses Th1 responses.
    • By convention, the antigens used for delayed-type hypersensitivity skin testing are injected intradermally into the volar surface of the forearm with a volume of 0.1 mL each. Erythema and induration are measured at 24, 48, and 72 hours. A reaction at 24 hours does not represent delayed-type hypersensitivity induced by cell-mediated immunity (CMI), or type IV reactivity. The Food and Drug Administration (FDA) –approved antigens for delayed-type hypersensitivity skin testing are limited to PPD of M tuberculosis and Candida.
    • Conventionally, children are tested with Candida and Dermatophytin in a 1:10 or 1:100 dilution and tested with tetanus in a 1:10 or 1:100 dilution of the diphtheria-tetanus (DT) vaccine. The higher dilution is used when the child has undergone a significant infection or unusually frequent immunization respectively.
    • Adults are initially tested with the 1:100 concentrations of these antigens.
    • When interpreting delayed-type hypersensitivity skin testing, whether adequate exposure to the antigens has taken place prior to the procedure must be considered. A vigorous immune response to one antigen, such as in measles infection, leads to the abrogation of other delayed-type hypersensitivity responses, for example, to purified protein derivative (PPD) even though the patient is also infected with tuberculosis.
    • Antigens that are poorly immunogenic in children and in some adults include mumps (no longer on the US market) and Trichophyton. Dinitrochlorobenzene (DNCB) and dinitrofluorobenzene (DNFB) have been superseded by in vitro assessments of cell-mediated immunity because of the risk of local tissue necrosis.
  • When an absent delayed-type hypersensitivity reaction is noted, screening tests for a T-cell disorder should include an absolute lymphocyte count and a chest radiograph to detect the thymus. Cell surface marker analysis of peripheral mononuclear cells by flow cytometry and in vitro lymphocyte proliferation responses against mitogens (polyclonal stimulants) and specific antigens are then performed.
  • Contact sensitivity to poison ivy and nickel is determined clinically; skin testing is not considered necessary.
  • Adverse drug reactions to antibiotics, phenytoin, and carbamazepine may involve nonimmune or immune-mediated mechanisms. The clinical setting of a reaction at 3 days or later with manifestation of a fixed rash with induration is more suspicious of involvement of a delayed-type hypersensitivity response.

Imaging Studies

  • A chest radiograph to determine whether the thymus is present is an appropriate screening test for T-cell disorders only in the newborn; however, the thymus may involute in stressed infants in the context of overwhelming infection or severe congenital cardiac disease.

Other Tests

  • When delayed-type hypersensitivity is absent and a T-cell disorder is suspected, assess in vitro lymphocyte proliferation responses against polyclonal stimulants such as mitogens (eg, phytohemagglutinins [PHA], concanavalin A [conA], pokeweed mitogen [PWM]) and specific antigens (eg, Candida, tetanus). Measurement of production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-12 in response to various stimulants can be helpful for screening mutations in IFNGR1, IFNGR2, STAT-1, IL12P40, or ILRB1 when such mutations are suspected. Low levels of one or more of these cytokines increase the likelihood of these mutations.
  • In patients with severe eczema, recurrent skin abscesses, elevated IgE, and history of frequent bone fractures, assessment of IL-17 production may be helpful. This is because patients with autosomal dominant hyper IgE syndrome have impaired development of Th17 cells, which is a major cellular source of IL-17.8
  • Cell surface markers for monocytes, T-cells (CD4, CD8, CD28, TCR a/b, TCR g/d), and activated T cells (CD25, HLA-DR, and CD5) are reported to be normal in IFNGR1, IL12P40,STAT1, IL12RB1, STAT3 mutations. In profound primary T-cell deficiencies such as severe combined immunodeficiency (SCID), the pattern of cell surface marker expression of lymphocyte and natural killer (NK) cells may identify the type of T-cell defect in conjunction with the clinical manifestations.
  • Mutational analysis for IFNGR1, IFNGR2, STAT-1,STAT-3, IL12P40, and IL12RB1 is available in specific research laboratories.
  • Additional genes that control downstream immune responses initiated by IFN-γ in the delayed-type hypersensitivity response are recognized; IFNGR2 does not bind IFN-γ but is needed for the activation of STAT-1 and its translocation to the nucleus.

Procedures

  • When disseminated bacille Calmette-Guérin (BCG) or nontuberculosis mycobacteria (NTM) is suspected, perform biopsy of infected sites in order to examine granuloma formation and detect acid-fast mycobacteria.
  • Tissue culture to detect mycobacteria is also indicated when disseminated BCG or NTM is suspected.

Histologic Findings

  • Granuloma formation in an intact delayed-type hypersensitivity response shows predominant infiltrates of activated macrophages and lymphocytes that can be identified as CD4+ T cells by immunohistochemical staining.
  • When NTM infection is present, multinucleated giant cells formed by fused activated macrophages are observed in the immunocompetent host.
  • In the patient with a T-cell defect, the formed granuloma lacks CD4+ T cells and these giant cells (due to ineffective macrophage activation by T cells). Instead, granulomatous lesions are characterized by infiltrate of polymorphonuclear cells, vacuolated cells, and macrophages.
  • Mycobacteria may be present in abundance but are not frequently stained, although they are isolated by culture techniques.

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.