Delayed Hypersensitivity Reactions

  • Author: Stuart L Abramson, MD, PhD; Chief Editor: Michael A Kaliner, MD  more...
Updated: Dec 23, 2015


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 is illustrated 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.[1] 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.



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 processed and presented to a T cell that has a specific receptor for that processed 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.




DTH reactions are extremely common. Persons of any age can be affected, but infants may not have the fully-developed immune capability to elicit a reaction.


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.

Contributor Information and Disclosures

Stuart L Abramson, MD, PhD Associate Professor of Pediatrics, Baylor College of Medicine; Consulting Staff, Allergy/Immunology Section, Texas Children's Hospital

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.

Michael R Simon, MD, MA Clinical Professor Emeritus, Departments of Internal Medicine and Pediatrics, Wayne State University School of Medicine; Professor, Department of Internal Medicine, Oakland University William Beaumont 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, Michigan State Medical Society, Michigan Allergy and Asthma Society, American College of Physicians, American Federation for Medical Research, Royal College of Physicians and Surgeons of Canada, Society for Experimental Biology and Medicine

Disclosure: Received ownership interest from Secretory IgA, Inc. for management position; Received ownership interest from siRNAx, Inc. for management position.

Chief Editor

Michael A Kaliner, MD Clinical Professor of Medicine, George Washington University School of Medicine; 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, Association of American Physicians

Disclosure: Nothing to disclose.

Additional Contributors

Melvin Berger, MD, PhD Adjunct Professor of Pediatrics and Pathology, Case Western Reserve University; Senior Medical Director, Clinical Research and Development, CSL Behring, LLC

Melvin Berger, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Allergy Asthma and Immunology, American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Clinical Investigation, Clinical Immunology Society

Disclosure: Received salary from CSL Behring for employment; Received ownership interest from CSL Behring for employment; Received consulting fee from America''s Health insurance plans for subject matter expert for clinical immunization safety assessment network acvtivity of cdc.


The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Walter Duane Hinshaw, DO; Gregory Paul Neyman, MD; and Stephen Mark Olmstead, DO; to the development and writing of this article.

  1. Malajian D, Belsito DV. Cutaneous delayed-type hypersensitivity in patients with atopic dermatitis. J Am Acad Dermatol. 2013 Apr 11. [Medline].

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

  3. Bansal R, Sharma PK. Exaggerated Mantoux reaction in a case of latent tuberculosis infection (LTBI). Indian J Tuberc. 2012 Jul. 59(3):171-3. [Medline].

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

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

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

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

  8. Wander K, Shell-Duncan B, Brindle E, O'Connor K. Predictors of delayed-type hypersensitivity to Candida albicans and anti-epstein-barr virus antibody among children in Kilimanjaro, Tanzania. Am J Phys Anthropol. 2013 Mar 4. [Medline].

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

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

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

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

  13. 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.

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

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

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

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

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

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

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

  21. 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.

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