Delayed Hypersensitivity Reactions 

Updated: May 07, 2018
Author: Stuart L Abramson, MD, PhD; Chief Editor: Michael A Kaliner, MD 

Overview

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 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 CD4 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.

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 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.

Epidemiology

Frequency

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.

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 self-limited rash to chronic debilitating diseases) based on the active disease present.

 

Presentation

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.[2, 3] 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.[4]  A positive Mantoux test is the result of the recruitment of several types of mononuclear leukocytes and the release of several cytokines that promote the DTH inflammatory reaction (see Pathophysiology section).  Measurement by the QuantiFERON test of interferon production by peripheral blood mononuclear cells has been used as an in vitro surrogate for the Mantoux test.

Granulomatous hypersensitivity reactions

Diseases in which delayed hypersensitivity is the major pathophysiological response include tuberculous leprosy, TB, sarcoidosis, and schistosomiasis. The inability to mount an adequate delayed hypersensitivity response results in a poor outcome in diseases such as leprosy and tuberculosis. 

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 sensitized to M tuberculosis by previous exposure 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.

 

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 responsible antigen.

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.[5, 6]

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 deficient cell-mediated immunity

If a deficiency in cell-mediated immunity is suggested, an anergy battery of skin tests can be performed.[7] 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.[8] 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 while 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 processed and presented to a T cell that has a specific receptor for that processed 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 Medscape Reference article for a full discussion (eg, see Dermatologic Manifestations of 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.

 

Medication

Medication Summary

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.[9]

Induction of a delayed hypersensitivity reaction may be used therapeutically. For example, alopecia areata may be treated by topical cutaneous sensitization to diphenylcyclopropenone at the affected sites. The reaction is maintained by repeated applications using a subsensitizing concentration.

Corticosteroids

Class Summary

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.

Mometasone (Elocon)

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

Prednisone (Deltasone, Orasone, Meticorten, Sterapred)

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

 

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.