Hypersensitivity Reactions, Delayed

Article Last Updated: Oct 18, 2005
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

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:

Physical

The physical examination findings can be normal, or they can reveal the signs and symptoms of the specific disease.

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.


DIFFERENTIALS


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


Lab Studies

Imaging Studies

Other Tests

Procedures

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.

Consultations

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

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.

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


FOLLOW-UP


Deterrence/Prevention

Complications

Prognosis

Patient Education


MISCELLANEOUS


Medical/Legal Pitfalls