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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

Walter Duane Hinshaw is a member of the following medical societies: American Academy of Family Physicians, American Osteopathic Association, and Texas Medical Association

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

Editors: Richard F Lockey, MD, Joy McCann Culverhouse Chair of Allergy and Immunology, Pediatrics and Public Health, James A Haley Veterans' Hospital, Director, Division of Allergy and Immunology, Professor of Medicine, University of South Florida College of Medicine; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine; Michael R Simon, MD, MA, Professor, Departments of Pediatrics and Internal Medicine, Department of Allergy and Immunology, Wayne State University School of Medicine; Consulting Staff, Henry Ford Health System; Timothy D Rice, MD, Departments of Internal Medicine and Pediatrics and Adolescent Medicine, Associate Professor, Saint Louis University School of Medicine; Michael A Kaliner, MD, Clinical Professor of Medicine, Section of Allergy and Immunology, Washington Hospital Center, George Washington University School of Medicine; Chief, Medical Director, Institute for Asthma and Allergy

Author and Editor Disclosure

Synonyms and related 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

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.



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. 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.

  • 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.



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



Lab 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.

    • 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. 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.



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



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.

Drug Category: Corticosteroids

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

Drug NameTriamcinolone (Aristocort)
DescriptionHelps treat inflammatory dermatosis responsive to steroids. Decreases inflammation by suppressing migration of PMN leukocytes and reversing capillary permeability.
Adult DoseTopical: 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 DoseAdminister as in adults; not for use >2 consecutive wk
ContraindicationsDocumented hypersensitivity; fungal, viral, or bacterial skin infections
InteractionsNone reported
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsDo 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

Drug NameMometasone (Elocon)
DescriptionMay depress formation, release, and activity of endogenous chemical mediators of inflammation.
Adult DoseApply sparingly to affected areas bid; do not use occlusive dressing; usually, do not use >2 consecutive wk
Pediatric DoseNot recommended but frequently used for short periods
ContraindicationsDocumented hypersensitivity; fungal, viral, or tubercular skin lesions; herpes simplex or zoster infections
InteractionsNone reported
PregnancyC - Safety for use during pregnancy has not been established.
PrecautionsIf used over large or denuded areas of body, for prolonged periods, with occlusive dressings, or in infants, adverse systemic effects may result

Drug NamePrednisone (Deltasone, Orasone, Meticorten, Sterapred)
DescriptionMay decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.
Adult Dose5-60 mg/d PO qd or divided bid/qid; taper over 2 wk as symptoms resolve
Pediatric Dose4-5 mg/m2/d PO; alternatively, 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve
ContraindicationsDocumented hypersensitivity; viral infection; peptic ulcer disease; hepatic dysfunction; connective tissue infections; fungal or tubercular skin infections; GI disease
InteractionsCoadministration 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
PregnancyB - Usually safe but benefits must outweigh the risks.
PrecautionsAbrupt 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



Deterrence/Prevention

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

Complications

  • Secondary infections such as cellulitis can occur.

Prognosis

  • Excellent

Patient Education

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



Medical/Legal Pitfalls

  • Misdiagnosis can result in inadequate or improper treatment.



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Hypersensitivity Reactions, Delayed excerpt

Article Last Updated: Oct 18, 2005