eMedicine Specialties > Allergy and Immunology > Allergy Pathogenesis

Hypersensitivity Reactions, Delayed: Differential Diagnoses & Workup

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

Differential Diagnoses

Human Bite Infections
Lymphoma, Cutaneous T-Cell
Mycosis Fungoides

Other Problems to Be Considered

Irritant dermatitis
Atopic eczema (atopic dermatitis)
Dermatitis herpetiformis
Chemical burn
Other lymphomas
Granulomatous hepatitis

Workup

Laboratory Studies

  • Contact dermatitis: No specific laboratory tests are needed unless the diagnosis is uncertain. Contact dermatitis is a clinical diagnosis. A skin biopsy can be performed if the diagnosis is in question, and the results of patch tests are often helpful to determine the specific contactant.
  • Tuberculin hypersensitivity skin reaction: No laboratory tests are needed. This is a specific local reaction to an administered Mantoux test.
  • Granulomatous diseases: Diagnostic testing differs depending on the disease suggested.
    • If TB is considered, a Mantoux test and a chest radiograph should be performed.3,4
    • If sarcoidosis is suggested, a chest radiograph and, if indicated, a biopsy, should be performed. An elevated serum angiotensin-converting enzyme level is not diagnostic.
    • If cutaneous lesions are possibly related to a granulomatous disease, then a skin biopsy can be performed.
  • Possible cell-mediated immunity: If a deficiency in cell-mediated immunity is suggested, an anergy battery of skin tests can be performed.5 Typically, the antigens used are candidin, trichophytin, mumps skin test antigen, and tetanus toxoid. If fewer than 4 recall antigens are used, the likelihood of a false-negative result is increased.
    • The concentrations used are candidin at 1:100 (vol:vol), trichophytin at 1:30 or 1:100 (vol:vol), mumps skin test antigen at 40 colony-forming units/mL, and tetanus toxoid at 0.2 Loeffler units/0.1 mL in 1:100 (vol:vol). The test volume is 0.1 mL placed intradermally. The maximum perpendicular diameters of induration are determined at 24, 48, and 72 hours. An immediate (20 min) wheal and flare at the injection site during a DTH skin test may result in a false-negative DTH reaction.
    • The term anergy is now expanded to imply an absence of the capacity to express DTH skin test reactivity to the antigens usually encountered (so-called recall antigens). The presence of anergy depends on the number and type of antigens used in the skin test evaluation, the smallest reaction considered to be positive, and other technical factors.
    • Most investigators use a panel of 4-5 antigens to which more than 90% of healthy adults exhibit at least one positive reaction. This percentage of reactors is understandably lower in healthy children because of a reduced opportunity for prior exposure to the microorganisms that normally result in such DTH reactivity.
    • Generally, the highest prevalence of reactions occurs against mumps, candidal, and tetanus antigens. Relative deficits are understandably more difficult to evaluate, but they are probably more common than absolute anergy in the biologic processes and clinical disorders described.
    • In some clinical situations, individuals may exhibit a deficit in expressing DTH reactions to particular antigens previously encountered, while other recall DTH responses are normal. Some controversy exists regarding whether the absence of reactivity to a tuberculin DTH skin test and normal responses to other recall antigens exclude previous or current infection with M tuberculosis. Reactivity to newly encountered antigens may not develop, but recall DTH reactivity is normal.
    • In more recent studies, investigators have focused on the cellular basis of anergy. With the aid of in vitro technology, abnormalities involving multiple components of the DTH apparatus have been described. The expression of DTH skin test reactivity requires the capacity to mount a cellular inflammatory reaction, a response frequently impaired nonspecifically in persons with chronic debilitating diseases. Moreover, other T-cell–dependent functions apparently are frequently impaired. Such deficits may either play an important role in the pathogenesis of a particular disease or occur as a consequence of that disease.
  • Laboratory correlate of the DTH skin test: Reactions include lymphocyte thymidine incorporation (ie, lymphocyte proliferation or blast transformation) following nonspecific stimulation with mitogens (eg, phytohemagglutinin, concanavalin A) or antigen stimulation. The mixed lymphocyte reaction is a thymidine incorporation T-cell reaction to cell surface antigens. Cytokine production from stimulated lymphocytes also may be measured.

Imaging Studies

  • If TB or sarcoidosis is suggested, chest radiographs and CT scans may be indicated.

Other Tests

  • Patch tests can be used for contact dermatitis in order to help determine the contactant.

Procedures

  • Skin biopsy may be indicated.

Histologic Findings

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 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.

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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