Delayed-type Hypersensitivity Clinical Presentation

  • Author: Harumi Jyonouchi, MD; Chief Editor: Russell W Steele, MD   more...
 
Updated: Aug 1, 2011
 

History

Delayed-type hypersensitivity (DTH) skin testing is usually performed to detect exposure to tuberculosis and, occasionally, when unusually extensive Candida infection has occurred. In these settings, the patient often has no prior history of unusually severe or opportunistic infections. In developing countries, ruling out confounding clinical malnutrition and rubeola infection that negate DTH skin test reactivity is crucial. HIV infection, sarcoidosis, and malignancies, such as Hodgkin lymphoma , also cause negate DTH responses.

Overwhelming infection such as sepsis is also known to cause suppresed delayed-type hypersensitivity responses. One study indicated that this is mediated by CD8+ regulatory T cells through a TRAIL-dependent mechanisms and these cells are induced by apoptotic cells.[13]

The presence of any cause for immunosuppression modifies the interpretation of tuberculin delayed-type hypersensitivity skin tests; in an immunosuppressive condition, 5-mm induration is interpreted as a positive response.

Delayed-type hypersensitivity skin reactions are absent in patients with lepromatous leprosy (M leprae), sarcoidosis, coccidioidomycosis, schistosomiasis, rheumatological diseases, severe viral infections (eg, influenza, mononucleosis, mumps), and those given the measles, mumps, rubella (MMR) vaccine recently (≤3 wk). Systemic steroid therapy can cause anergy; however, inhaled steroids with high bioavailability could also decrease delayed-type hypersensitivity reactions and less frequently produce anergy when administered in large doses. Longer duration (>2 wk) and higher doses of steroids increase the risk for anergy, but no exact doses or duration predict induction of anergy in a given individual.

Other immunosuppressive agents that cause anergy include cancer chemotherapy agents, calcineurin inhibitors, and monoclonal antibodies against the immune system such as anti-TNF and anti-CD20 agents.

Usually, a patient with anergy caused by a T-cell immunodeficiency can be identified before wasting sets in. A pattern of unusually frequent or severe common infections, extensive mucocutaneous candidiasis, or dermatitis together with lymphopenia raises the suspicion of severe combined immunodeficiency (SCID) or another severe T-cell immunodeficiency.

A patient with disseminated bacille Calmette-Guérin (BCG) or nontuberculosis mycobacteria (NTM) infection may have a history of consanguinity or familial infection indicating autosomal recessive genetic disorders. It is necessary to evaluate these patients for IFNGR1, IFNGR2, STAT-1, IL12P40, and IL12RB1 mutations. Patients with BCG infection usually present in early infancy after administration of the BCG vaccine. NTM infection develops more typically in mid childhood when community exposure to these mycobacteria occurs. A patient with one of the above mutations responds poorly to appropriate antimycobacterial therapy and often has a fulminant fatal infection.

Nontyphus Salmonella infections are more frequently observed in patients with the above-described disorders. Asthma, atopy, and immune complex disease (eg, glomerulonephritis, vasculitis, positive rheumatoid factors) are sometimes present.

Repetitive delayed-type hypersensitivity skin testing does not change the parameters used to define a positive test result.

Delayed-type hypersensitivity antigens for coccidioidomycosis are no longer available. Diagnosis depends on identifying the organism or serology. Negative skin test reactivity to coccidioidin does correlate with a less favorable clinical outcome. However, the positive skin test result usually persists following an initial infection so that recurrence cannot be determined by the delayed-type hypersensitivity skin testing.

Delayed-type hypersensitivity skin test reactivities for histoplasmosis and blastomycosis cross-react. In addition, positive delayed-type hypersensitivity skin reactions in exposed but not infected individuals living in endemic areas confound interpretation. Both fungal infections have increased in incidence in HIV patients; these patients are frequently anergic. Diagnosis now requires culturing the organism, antigen/DNA detection, and/or serologic confirmation.

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Physical

The delayed-type hypersensitivity response in the skin is determined by the extent of induration. Erythema indicates an immediate hypersensitivity reaction and begins earlier than induration but often persists even after induration has developed.

Delayed-type hypersensitivity skn test to most antigens is read as positive when induration is 5 mm or more at 48 hours and 72 hours following inoculation. For tuberculin, 15 mm is considered a positive response for persons aged 4 years or older without risk factors; 10 mm is considered a positive response for younger children and those in populations with increased exposure or in whom immunosuppression is likely. A tuberculin reaction of 5 mm is considered positive when clinical evidence of tuberculosis, HIV infection, or close contact with people with infectious tuberculosis is noted.

Disseminated BCG and NTM infection are characterized by fever, wasting, lymphadenopathy, and hepatosplenomegaly.

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Causes

A positive delayed-type hypersensitivity response to the purified protein derivative (PPD) of M tuberculosis is elicited 4-6 weeks after exposure to tuberculosis. Populations at increased risk for tuberculosis include immigrants from countries with a high incidence of tuberculosis, such as African, Asian, and South American countries, and those with HIV infection. High-risk populations in the United States include those who are incarcerated, those who are homeless, migrant workers, and those who use illicit drugs. Individuals who are exposed to these populations are also at increased risk.

Anergy is discussed under History and Pathophysiology.

A single functional mature T cell can transfer delayed-type hypersensitivity reactions; thus, a patient who received hematopoietic stem cell transplant from a donor with positive delayed-type hypersensitivity responses to the specific antigen could reveal positive delayed-type hypersensitivity responses to the same antigen.

Contact delayed-type hypersensitivity reactions occur in patients with poison ivy and nickel hypersensitivity

Delayed-type hypersensitivity to sulfonamides, phenytoin, and carbamazepine has been described. Reactions to penicillin-type antibiotics may be cell-mediated, but immunoglobulin G (IgG)-mediated responses are much more common.

Genetic factors in contact hypersensitivity (CH) are not well understood but studies targeting candidate genes revealed association of single nucleotide polymorphisms of some candidate genes in development of CH. These genes include NAT1, NAT2, GSTT, ACE, TNF, and IL-16.[14]

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Contributor Information and Disclosures
Author

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.

Specialty Editor Board

Terry W Chin, MD, PhD  Associate Director, Pediatric Allergy/Immunology/Pulmonology, Miller Children's Hospital, Long Beach Memorial Medical Center; Associate Professor, Department of Pediatrics, University of California, Irvine, School of Medicine

Terry W 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.

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.

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.

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

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: Nothing to disclose.

Additional Contributors

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.

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. [Best Evidence] Adam J, Pichler WJ, Yerly D. Delayed drug hypersensitivity: models of T-cell stimulation. Br J Clin Pharmacol. May 2011;71(5):701-7. [Medline].

  4. 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].

  5. 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].

  6. Pennino D, Eyerich K, Scarponi C, Carbone T, Eyerich S, Nasorri F. IL-17 amplifies human contact hypersensitivity by licensing hapten nonspecific Th1 cells to kill autologous keratinocytes. J Immunol. May 1 2010;184(9):4880-8. [Medline].

  7. 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].

  8. Oboki K, Ohno T, Kajiwara N, Arae K, Morita H, Ishii A. IL-33 is a crucial amplifier of innate rather than acquired immunity. Proc Natl Acad Sci U S A. Oct 26 2010;107(43):18581-6. [Medline].

  9. [Best Evidence] Frenzel DF, Weiss JM. Osteopontin and allergic disease: pathophysiology and implications for diagnostics and therapy. Expert Rev Clin Immunol. Jan 2011;7(1):93-109. [Medline].

  10. 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].

  11. 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].

  12. Schimke LF, Sawalle-Belohradsky J, Roesler J, Wollenberg A, Rack A, Borte M. Diagnostic approach to the hyper-IgE syndromes: immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis. J Allergy Clin Immunol. Sep 2010;126(3):611-7.e1. [Medline].

  13. Unsinger J, Kazama H, McDonough JS, Griffith TS, Hotchkiss RS, Ferguson TA. Sepsis-induced apoptosis leads to active suppression of delayed-type hypersensitivity by CD8+ regulatory T cells through a TRAIL-dependent mechanism. J Immunol. Jun 15 2010;184(12):6766-72. [Medline].

  14. [Best Evidence] Schnuch A, Westphal G, Mössner R, Uter W, Reich K. Genetic factors in contact allergy--review and future goals. Contact Dermatitis. Jan 2011;64(1):2-23. [Medline].

  15. 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].

  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. [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].

  18. 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].

  19. 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].

  20. 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].

  21. 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.

  22. 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].

  23. 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].

  24. 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].

  25. 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].

  26. 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].

  27. 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].

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

  29. 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].

  30. 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].

  31. 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].

  32. 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].

  33. 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].

  34. 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].

  35. 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].

  36. 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].

  37. 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].

  38. 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].

  39. 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].

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

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

  42. 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].

  43. 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].

  44. 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].

 
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