eMedicine Specialties > Allergy and Immunology > Allergy Pathogenesis

Hypersensitivity Reactions, Delayed

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
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

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.

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.

Treatment

Medical Care

Medical treatment is specific for the disease entity. Some common examples follow.

• Contact dermatitis: The treatment of contact dermatitis varies depending on the severity of the disease. The best advice is to avoid the offending antigen. Pharmaceutical treatment varies, including over-the-counter corticosteroid preparations, prescription corticosteroid preparations, injectable corticosteroids, oral corticosteroids, and Burow solution.
• Tuberculin hypersensitivity skin reactions: Treatment is rarely needed because this response is usually short-lived and self-limited. Topical corticosteroid preparations can be applied as needed. On rare occasions, the reaction to a delayed hypersensitivity skin test may be extreme and result in axillary lymphadenopathy and fever. Such reactions are self-limited and may be treated with an antipyretic medication such as aspirin or ibuprofen.
• Granulomatous diseases: Treatment varies greatly depending on the specific disease. Refer to the appropriate eMedicine article for a full discussion (eg, see Sarcoidosis or Crohn Disease).

Consultations

Whether or not to consult a specialist and which specialist to consult also depend on the specific disease and its severity.

• Contact dermatitis: Most cases of contact dermatitis can be managed in an outpatient setting by a primary care physician. However, for severe cases, immediate consultation with a physician board-certified in allergy and immunology and/or dermatology is warranted.
• Tuberculin hypersensitivity skin reactions: If the Mantoux reaction is positive, patients may require consultation with a pulmonologist or an infectious disease specialist. A primary care physician trained in assessing the significance of a positive Mantoux reaction can also effectively treat these patients.
• Granulomatous diseases: Depending on the specific disease entity, an infectious disease specialist (eg, TB, fungal disease, schistosomiasis), pulmonologist (eg, TB, sarcoidosis), gastroenterologist (eg, granulomatous hepatitis, Crohn disease), and/or an allergist/clinical immunologist may need to be consulted.

Activity

As tolerated

Medication

Medical treatment differs greatly depending on the specific disease entity. Only a few medications are discussed. In addition to drugs mentioned below, a drug that may augment cell-mediated immunity is cimetidine, which is an H2 receptor blocker that acts as a reverse antagonist and may augment cell-mediated immunity.⁶

Corticosteroids

Have anti-inflammatory properties and cause profound and varied metabolic effects. Modify the body's immune response to diverse stimuli.

Triamcinolone (Aristocort)

Helps treat inflammatory dermatosis responsive to steroids. Decreases inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability.

Dosing

Adult

Topical: Apply a thin film bid/tid until a favorable response is obtained; not for use >3 consecutive wk
Alternatively, 40-80 mg IM once
Strength of dose should be individualized for patient

Pediatric

Administer as in adults; not for use >2 consecutive wk

Interactions

None reported

Contraindications

Documented hypersensitivity; fungal, viral, or bacterial skin infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not use in patients with decreased skin circulation; avoid using on face, neck, axillae, and groin; prolonged use, applications over large areas, and use of potent steroids and occlusive dressings may cause systemic absorption; systemic absorption may cause Cushing syndrome, reversible HPA axis suppression, hyperglycemia, and glycosuria

Mometasone (Elocon)

May depress formation, release, and activity of endogenous chemical mediators of inflammation.

Dosing

Adult

Apply sparingly to affected areas bid; do not use occlusive dressing; usually, do not use >2 consecutive wk

Pediatric

Not recommended but frequently used for short periods

Interactions

None reported

Contraindications

Documented hypersensitivity; fungal, viral, or tubercular skin lesions; herpes simplex or zoster infections

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

If used over large or denuded areas of body, for prolonged periods, with occlusive dressings, or in infants, adverse systemic effects may result

Prednisone (Deltasone, Orasone, Meticorten, Sterapred)

May decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

Dosing

Adult

5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve

Pediatric

4-5 mg/m²/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve

Interactions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and rifampin may increase metabolism of glucocorticoids (consider increasing maintenance dose); monitor for hypokalemia with coadministration of diuretics

Contraindications

Documented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Follow-up

Deterrence/Prevention

• Avoiding offending agents requires the identification of Rhus toxicodendron plants.

Complications

• Secondary infections such as cellulitis can occur.

Prognosis

• The prognosis for delayed-type hypersensitivity reactions is excellent.

Patient Education

• Encourage patients to learn about the different species within the Rhus genus of plants. Most encyclopedias contain this information.

Miscellaneous

Medicolegal Pitfalls

• Misdiagnosis can result in inadequate or improper treatment.

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. 14^th 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. 4^th 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. 5^th 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. 5^th ed. St. Louis, Mo: Mosby-Year Book; 1998.

16. Roitt IM. Essential Immunology. 9^th 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.

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

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

The authors and editors of eMedicine 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.

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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