eMedicine Specialties > Allergy and Immunology > Allergy Pathogenesis

Hypersensitivity Reactions, Delayed

Author: Walter Duane Hinshaw, DO, Clinical Associate Professor, Consulting Staff, Family Medicine, University of North Texas Health Science Center at Fort Worth, Baylor University Medical Center at Garland
Coauthor(s): Gregory Paul Neyman, MD, Resident, Family Practice, Family Practice Resident Physician, Covenant Medical Center; Stephen Mark Olmstead, DO, Division of Allergy and Immunology, Assistant Clinical Professor, Department of Internal Medicine, University of Texas Southwestern Medical Center
Contributor Information and Disclosures

Updated: Jun 2, 2009

Introduction

Background

Delayed hypersensitivity reactions are inflammatory reactions initiated by mononuclear leukocytes. The term delayed is used to differentiate a secondary cellular response, which appears 48-72 hours after antigen exposure, from an immediate hypersensitivity response, which generally appears within 12 minutes of an antigen challenge. These reactions are mediated by T cells and monocytes/macrophages rather than by antibodies. They are also termed type IV hypersensitivity reactions.

Delayed hypersensitivity is a major mechanism of defense against various intracellular pathogens, including mycobacteria, fungi, and certain parasites, and it occurs in transplant rejection and tumor immunity. The central role of CD4+ T cells in delayed hypersensitivity manifests in patients with AIDS. Because of the loss of CD4+ cells, the host response against intracellular pathogens such as Mycobacterium tuberculosis is markedly impaired. The bacteria are engulfed by macrophages but are not killed.

If T-cell function is abnormal, the patient presents with opportunistic infections, including infection with mycobacteria, fungi, parasites, and, often, mucocutaneous candidiasis. Undesirable consequences of delayed-type hypersensitivity (DTH) reactions include illness such as contact dermatitis and allograft rejection. Examples of DTH reactions are contact dermatitis (eg, poison ivy rash), tuberculin skin test reactions, granulomatous inflammation (eg, sarcoidosis, Crohn disease), allograft rejection, graft versus host disease, and autoimmune hypersensitivity reactions. Of note, the Rhus genus of plants, which includes poison ivy, poison oak, and poison sumac, all cause identical rashes.

Pathophysiology

The cellular events that result in delayed hypersensitivity reactions primarily involve T cells and macrophages. First, local immune and inflammatory responses at the site of foreign antigen up-regulate endothelial cell adhesion molecule expression, promoting the accumulation of leukocytes at the tissue site. The antigen is engulfed by macrophages and monocytes and is presented to a T cell that has a specific receptor for that antigen. Macrophages secrete interleukin (IL)–1, IL-2, IL-6, and other lymphokines. Cytotoxic T cells can also be activated. The recruited macrophages can form giant cells. The characteristic histologic appearance of the macrophage–T-cell infiltrate is a granuloma. This type of infiltrate in the tissue is called granulomatous inflammation.

Several variants of DTH exist, and their precise pathophysiologic mechanisms are slightly different. For example, in contact hypersensitivity reactions, the epidermis is involved; in pulmonary tuberculosis (TB), lung tissue is involved.

Frequency

International

DTH reactions are extremely common.

Mortality/Morbidity

Delayed hypersensitivity reactions are normal physiological events. Anything that alters these normal events can lead to multiple opportunistic infections. DTH reactions may include, but are not limited to, contact dermatitis (eg, poison ivy rash), tuberculin skin test reactions, granulomatous inflammation (eg, sarcoidosis, Crohn disease), allograft rejection, graft versus host disease, and autoimmune hypersensitivity reactions. Morbidity and mortality vary (eg, ranging from a rash to chronic debilitating diseases) based on the active disease present.

Race

No racial predilection is recognized.

Sex

No sexual predilection is recognized.

Age

Persons of any age can be affected.

Clinical

History

The clinical history of delayed hypersensitivity reactions differs depending on the etiology. Some of the more common examples are as follows:

  • Contact hypersensitivity (ie, allergic contact dermatitis)
    • Patients often report being in wooded areas or having made contact with poison ivy or poison oak, which caused a rash, itching, or both.
    • The exposure occurs 48-72 hours before the development of symptoms.
  • Tuberculin hypersensitivity reactions
    • Many times during a routine health screening, patients have a positive Mantoux test result and are asymptomatic. In these cases, patients may recall being exposed to someone with TB or with a chronic cough. In many cases, patients do not recall a possible exposure.
    • The Mantoux test itself is a delayed hypersensitivity reaction.1 Thus, 48-72 hours following the intradermal administration of purified M tuberculosis protein derivative, patients who have been exposed to the bacteria develop a delayed hypersensitivity reaction manifested by inflammation and edema in the dermis.2
  • Granulomatous hypersensitivity reactions: Diseases in which delayed hypersensitivity is the major pathophysiological response include tuberculous leprosy, TB, sarcoidosis, and schistosomiasis.

Physical

The physical examination findings can be normal, or they can reveal the signs and symptoms of the specific disease.

  • Contact hypersensitivity: Examination usually reveals edematous and erythematous epidermal tissue with microvesicles. If the offending antigen is from the Rhus genus of plants, the involved area usually appears in a linear fashion. If the offending antigen is nickel (eg, jewelry), then the involved area is oriented in a fashion consistent with the area of contact. Long-term nickel exposure results in an eczematous dermatitis with lichenification of the skin.
  • Tuberculin hypersensitivity reactions: Approximately 48-72 hours following the intradermal administration of purified M tuberculosis protein, patients who have been exposed to M tuberculosis develop an area of erythema and induration.
  • Granulomatous hypersensitivity reactions: The physical examination findings differ depending on the underlying disease. For example, if the patient has active TB, then a chronic cough, malaise, night sweats, weight loss, and pyrexia are present.

Causes

Delayed hypersensitivity reactions are normal physiological events. Anything that alters these normal events can lead to multiple opportunistic infections. Immune deficiencies (congenital or acquired) and immunosuppressive agents can alter this normal response.

More on Hypersensitivity Reactions, Delayed

Overview: Hypersensitivity Reactions, Delayed
Differential Diagnoses & Workup: Hypersensitivity Reactions, Delayed
Treatment & Medication: Hypersensitivity Reactions, Delayed
Follow-up: Hypersensitivity Reactions, Delayed
References
Further Reading
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References

  1. Olivier C. [Intradermal tuberculin test]. Arch Pediatr. Jun 2000;7 Suppl 3:559s-564s. [Medline].

  2. Facktor MA, Bernstein RA, Fireman P. Hypersensitivity to tetanus toxoid. J Allergy Clin Immunol. Jul 1973;52(1):1-12. [Medline].

  3. Chadha VK. Tuberculin test. Indian J Pediatr. Jan 2001;68(1):53-8. [Medline].

  4. Rigouts L. Clinical practice : Diagnosis of childhood tuberculosis. Eur J Pediatr. Apr 25 2009;[Medline].

  5. Wilson JD. Skin testing in the assessment of cell-mediated immunity. N Z Med J. Jan 26 1977;85(580):41-4. [Medline].

  6. Jorizzo JL, Sams WM, Jegasothy BV, Olansky AJ. Cimetidine as an immunomodulator: chronic mucocutaneous candidiasis as a model. Ann Intern Med. Feb 1980;92(2 Pt 1):192-5. [Medline].

  7. Cohen DE, Brancaccio RR, Soter NA. Diagnostic tests for type IV or delayed hypersensitivity reactions. Clin Allergy Immunol. 2000;15:287-305. [Medline].

  8. Fauci AJ, Braunwald E, Isselbacher KJ, et al, eds. Harrison's Principles of Internal Medicine. 14th ed. New York, NY: McGraw-Hill; 1998.

  9. Gifford RR, Hatfield SM, Schmidtke JR. Cimetidine-induced augmentation of human lymphocyte blastogenesis by mitogen, bacterial antigen, and alloantigen. Transplantation. Feb 1980;29(2):143-8. [Medline].

  10. Goroll AH, May LA, Mulley AG, eds. Primary Care Medicine: Office Evaluation and Management of the Adult Patient. 4th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2000.

  11. Hyman MH. Delayed drug hypersensitivity reactions. Ann Intern Med. May 4 2004;140(9):W35; author reply W36. [Medline].

  12. Jacysyn JF, Abrahamsohn IA, Macedo MS. Modulation of delayed-type hypersensitivity during the time course of immune response to a protein antigen. Immunology. Mar 2001;102(3):373-9. [Medline].

  13. Jelinek C. Appendix E: Diagnostic Procedures. Delayed Hypersensitivity Skin Testing. In: Allergy/Immunology Specialist Course Manual. 5th ed. US Army; 1990:E-1-11.

  14. Kusy RP. Clinical response to allergies in patients. Am J Orthod Dentofacial Orthop. May 2004;125(5):544-7. [Medline].

  15. Middleton E Jr, Reed CE, Ellis EF, et al, eds. Allergy: Principles and Practice. 5th ed. St. Louis, Mo: Mosby-Year Book; 1998.

  16. Roitt IM. Essential Immunology. 9th ed. Oxford, UK: Blackwell Scientific; 1998:Chapters 22-23.

  17. Simon MR, Salberg DJ, Crane SA. In vivo cimetidine augmentation of phytohemagglutinin-induced human lymphocyte thymidine uptake. Transplantation. May 1981;31(5):400-2. [Medline].

  18. Slavin RG, Tennenbaum JI, Becker RJ, et al. Cell transfer of delayed hypersensitivity to ragweed from atopic subjects treated with emulsified ragweed extracts. J Allergy. 1963;34:368-73.

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Further Reading

Relevant guidelines
Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC.
Centers for Disease Control and Prevention (CDC). Guidelines for the investigation of contacts of persons with infectious tuberculosis. Recommendations from the National Tuberculosis Controllers Association and CDC. MMWR Recomm Rep 2005 Dec 16;54(RR-15):1-47.

Guidelines for infection control in dental health-care settings-2003.
Kohn WG, Collins AS, Cleveland JL, Harte JA, Eklund KJ, Malvitz DM. Guidelines for infection control in dental health-care settings--2003. MMWR Recomm Rep 2003 Dec 19;52(RR-17):1-61.

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Keywords

classic delayed-type hypersensitivity reaction, type IV hypersensitivity reaction, cell-mediated hypersensitivity reaction, delayed-type hypersensitivity, DTH, delayed hypersensitivity, allergic reaction, delayed allergic reaction, hypersensitivity, allergy, allergies, transplant rejection, tumor immunity, transplantation reaction, transplant reaction, transplantation rejection, contact dermatitis, allograft rejection, poison ivy, poison oak, poison sumac, tuberculin skin test reactions, granulomatous inflammation, sarcoidosis, Crohn disease, allograft rejection, graft-versus-host disease, GVHD, graft versus host disease, autoimmune hypersensitivity reaction, inflammatory response, allergic dermatitis, rash, skin rash, anergy, delayed hypersensitivity reactions

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Contributor Information and Disclosures

Author

Walter Duane Hinshaw, DO, Clinical Associate Professor, Consulting Staff, Family Medicine, University of North Texas Health Science Center at Fort Worth, Baylor University Medical Center at Garland
Disclosure: Nothing to disclose.

Coauthor(s)

Gregory Paul Neyman, MD, Resident, Family Practice, Family Practice Resident Physician, Covenant Medical Center
Disclosure: Nothing to disclose.

Stephen Mark Olmstead, DO, Division of Allergy and Immunology, Assistant Clinical Professor, Department of Internal Medicine, University of Texas Southwestern Medical Center
Disclosure: Nothing to disclose.

Medical Editor

Richard F Lockey, MD, University Distinguished Health Professor, Professor of Medicine, Pediatrics and Public Health, Joy McCann Culverhouse Chair in Allergy and Immunology, University of South Florida College of Medicine; Director, Division of Allergy and Immunology, James A Haley Veterans' Hospital
Richard F Lockey, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Association for the Advancement of Science, American College of Chest Physicians, American College of Occupational and Environmental Medicine, American College of Physicians, American Medical Association, and Florida Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

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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