Allergic and other hypersensitivity disorders are inappropriate or exaggerated immune reactions. Inappropriate immune reactions include those that are misdirected against intrinsic body components, leading to autoimmune disorders (see Autoimmune Disorders). Allergic and atopic disorders involve exaggerated immune responses to foreign antigens.
Classification of Hypersensitivity Reactions
Hypersensitivity reactions are divided into 4 types by the Gell and Coombs classification. Hypersensitivity disorders often involve more than 1 type.
Type I reactions (immediate hypersensitivity) are IgE-mediated. Antigen binds to IgE that is bound to tissue mast cells and blood basophils, triggering release of preformed mediators (eg, histamine, proteases, chemotactic factors) and synthesis of other mediators (eg, prostaglandins, leukotrienes, platelet-activating factor, cytokines). These mediators cause vasodilation, increased capillary permeability, mucus hypersecretion, smooth muscle spasm, and tissue infiltration with eosinophils, type 2 helper T (TH2) cells, and other inflammatory cells.
Type I reactions underlie atopic disorders (eg, allergic asthma, rhinitis, conjunctivitis), anaphylaxis, some cases of angioedema, urticaria, and latex and some food allergies. Type I reactions develop < 1 h after exposure to antigen.
Type II reactions (antibody-dependent cytotoxic hypersensitivity) result when antibody binds to cell surface antigens or to a molecule coupled to a cell surface. The antigen-antibody complex activates cells that participate in antibody-dependent cell-mediated cytotoxicity (eg, natural killer cells, eosinophils, macrophages), complement, or both. The result is cell and tissue damage.
Disorders involving type II reactions include hyperacute graft rejection of an organ transplant, Coombs-positive hemolytic anemias, Hashimoto thyroiditis, and anti–glomerular basement membrane disease (eg, Goodpasture syndrome).
Type III reactions (immune complex disease) cause inflammation in response to circulating antigen-antibody immune complexes deposited in vessels or tissue. These complexes can activate the complement system or bind to and activate certain immune cells, resulting in release of inflammatory mediators. Consequences of immune complex formation depend in part on the relative proportions of antigen and antibody in the immune complex. Early, there is excess antigen with small antigen-antibody complexes, which do not activate complement. Later, when antigen and antibody are more balanced, immune complexes are larger and tend to be deposited in various tissues (eg, glomeruli, blood vessels), causing systemic reactions. The isotype of induced antibodies changes, and glycosylation, size, and charge of the complex's components contribute to the clinical response.
Type III disorders include serum sickness, SLE, RA, leukocytoclastic vasculitis, cryoglobulinemia, hypersensitivity pneumonitis, and several types of glomerulonephritis. Type III reactions develop 4 to 10 days after exposure to antigen and, if exposure to the antigen continues, can become chronic.
Type IV reactions (delayed hypersensitivity) are T-cell–mediated.
T cells, sensitized after contact with a specific antigen, are activated by reexposure to the antigen; they damage tissue by direct toxic effects or through release of cytokines, which activate eosinophils, monocytes and macrophages, neutrophils, or natural killer cells.
Disorders involving type IV reactions include contact dermatitis (eg, poison ivy), hypersensitivity pneumonitis, allograft rejection, the immune response to TB, and many forms of drug hypersensitivity.
Atopic and Allergic Disorders
Type I hypersensitivity reactions (see Type I) underlie all atopic and many allergic disorders. The terms atopy and allergy are often used interchangeably but are different:
Thus, all atopic disorders are considered allergic, but many allergic disorders (eg, hypersensitivity pneumonitis) are not atopic. Allergic disorders are the most common disorders among people.
Atopic disorders most commonly affect the nose, eyes, skin, and lungs. These disorders include extrinsic atopic dermatitis, immune-mediated urticaria (see Urticaria), immune-mediated angioedema, acute latex allergy (see Sidebar 1: Latex Sensitivity), some allergic lung disorders (eg, some cases of asthma, IgE-mediated components of allergic bronchopulmonary aspergillosis), allergic rhinitis, and allergic reactions to venomous stings.
Complex genetic, environmental, and site-specific factors contribute to development of allergies.
Genetic factors may be involved, as suggested by familial inheritance of disease, association between atopy and specific HLA loci, and polymorphisms of several genes, including those for the high-affinity IgE receptor β-chain, IL-4 receptor α-chain, IL-4, IL-13, CD14, dipeptidyl-peptidase 10 (DPP10), and a disintegrin and metalloprotease domain 33 (ADAM33).
Environmental factors interact with genetic factors to maintain type 2 helper T (TH2) cell–directed immune responses. TH2 cells activate eosinophils, promote IgE production, and are proallergic. Early childhood exposure to bacterial and viral infections and endotoxins (eg, lipopolysaccharide) may normally shift native TH2-cell responses to type 1 helper T (TH1)–cell responses, which suppress TH2 cells and therefore discourage allergic responses. Regulatory T (CD4+CD25+Foxp3+; Treg) cells (which are capable of suppressing TH2-cell responses) and IL-12–secreting dendritic cells (which drive TH1-cell responses) are perhaps also involved. But trends in developed countries toward smaller families with fewer children, cleaner indoor environments, and early use of antibiotics may limit children's exposure to the infectious agents that drive a predominantly TH1-cell response; such trends may explain the increased prevalence of some allergic disorders. Other factors thought to contribute to allergy development include chronic allergen exposure and sensitization, diet, and environmental pollutants.
Site-specific factors include adhesion molecules in bronchial epithelium and skin and molecules in the GI tract that direct TH2 cells to target tissues.
By definition, an allergen induces type I IgE-mediated or type IV T-cell–mediated immune responses. Allergic triggers are almost always low molecular weight proteins; many of them can become attached to airborne particles.
Allergens that most commonly cause acute and chronic allergic reactions include
When allergen binds to IgE-sensitized mast cells and basophils, histamine is released from their intracellular granules. Mast cells are widely distributed but are most concentrated in skin, lungs, and GI mucosa; histamine facilitates inflammation and is the primary mediator of clinical atopy. Physical disruption of tissue and various substances (eg, tissue irritants, opiates, surface-active agents, complement components C3a and C5a) can trigger histamine release directly, independent of IgE.
Histamine causes the following:
When released systemically, histamine is a potent arteriolar dilator and can cause extensive peripheral pooling of blood and hypotension; cerebral vasodilation may be a factor in vascular headache. Histamine increases capillary permeability; the resulting loss of plasma and plasma proteins from the vascular space can worsen circulatory shock. This loss triggers a compensatory catecholamine surge from adrenal chromaffin cells.
Symptoms and Signs
Common symptoms include
Signs may include nasal turbinate edema, sinus pain during palpation, wheezing, conjunctival hyperemia and edema, urticaria, angioedema, dermatitis, and skin lichenification. Stridor, wheezing, and hypotension are life-threatening signs of anaphylaxis (see Anaphylaxis).
A thorough history is generally more reliable than testing or screening. History should include
Age at onset may be important in asthma because childhood asthma is likely to be atopic and asthma beginning after age 30 is not. Health care workers may be unaware that exposure to latex products could be causing their allergic reaction.
Certain tests can suggest but not confirm an allergic origin of symptoms.
CBC may be done to detect eosinophilia if patients are not taking corticosteroids, which reduce the eosinophil count. However, CBC is of limited value because although eosinophils may be increased in atopy or other conditions (eg, drug hypersensitivity, cancer, some autoimmune disorders, parasitic infection), a normal eosinophil count does not exclude allergy. Total WBC is usually normal. Anemia and thrombocytosis are not typical of allergic responses and should prompt consideration of a systemic inflammatory disorder.
Conjunctival or nasal secretions or sputum can be examined for leukocytes; finding any eosinophils suggests that TH2-mediated inflammation is likely.
Serum IgE levels are elevated in atopic disorders but are of little help in diagnosis because they may also be elevated in parasitic infections, infectious mononucleosis, autoimmune disorders, drug reactions, immunodeficiency disorders (hyper-IgE syndrome—see Hyper-IgE Syndrome—and Wiskott-Aldrich syndrome—see Wiskott-Aldrich Syndrome), and in some forms of multiple myeloma. IgE levels are probably most helpful for following response to therapy in allergic bronchopulmonary aspergillosis (see Allergic Bronchopulmonary Aspergillosis (ABPA)).
Skin testing uses standardized concentrations of antigen introduced directly into skin and is indicated when a detailed history and physical examination do not identify the cause and triggers for persistent or severe symptoms. Skin testing has higher positive predictive values for diagnosing allergic rhinitis and conjunctivitis than for diagnosing allergic asthma or food allergy; negative predictive value for food allergy is high. The most commonly used antigens are pollens (tree, grass, weed), molds, house dust mites, animal danders and sera, insect venom, foods, and β-lactam antibiotics. Choice of antigens to include is based on patient history and geographic prevalence.
Two skin test techniques can be used:
The prick test can detect most common allergies. The intradermal test is more sensitive but less specific; it can be used to evaluate sensitivity to allergens when prick test results are negative or equivocal.
For the prick test, a drop of antigen extract is placed on the skin, which is then tented up and pricked or punctured through the extract with the tip of a 27-gauge needle held at a 20° angle or with a commercially available prick device.
For the intradermal test, just enough extract to produce a 1- or 2-mm bleb (typically 0.02 mL) is injected intradermally with a 0.5- or 1-mL syringe and a 27-gauge short-bevel needle.
Prick and intradermal skin testing should include the diluent alone as a negative control and histamine (10 mg/mL for prick tests, 0.01 mL of a 1:1000 solution for intradermal tests) as a positive control. For patients who have had a recent (< 1 yr) generalized reaction to the test antigen, testing begins with the standard reagent diluted 100-fold, then 10-fold, and then the standard concentration. A test is considered positive if a wheal and flare reaction occurs and wheal diameter is 3 to 5 mm greater than that of the negative control after 15 to 20 min. False positives occur in dermatographism (a wheal and flare reaction provoked by stroking or scraping the skin). False negatives occur when allergen extracts have been stored incorrectly or are outdated. Certain drugs can also interfere with results and should be stopped a few days to a week before testing. These drugs include OTC and prescription antihistamines, tricyclic antidepressants, and monoamine oxidase inhibitors. Some clinicians suggest that testing should be avoided in patients taking β-blockers because these patients are more likely to have risk factors for severe reactions. These risk factors tend to predict limited cardiopulmonary reserve and include coronary artery disease, arrhythmias, and older age. Also, β-blockers can interfere with treatment of severe reactions by blocking response to β-adrenergic agonists such as epinephrine.
Allergen-specific serum IgE tests use an enzyme-labeled anti-IgE antibody to detect binding of serum IgE to a known allergen. They are done when skin testing might be ineffective or risky—for example, when drugs that interfere with test results cannot be temporarily stopped before testing or when a skin disorder such as eczema or psoriasis would make skin testing difficult. For allergen-specific serum IgE tests, the allergen is immobilized on a synthetic surface. A substrate for the enzyme is then added; the substrate provides colorimetric fluorescent or chemiluminescent detection of binding. Allergen-specific IgE tests have replaced radioallergosorbent testing (RAST), which used 125I-labeled anti-IgE antibody. Although the allergen-specific serum IgE tests are not radioactive, they are still sometimes referred to as RAST.
Provocative testing involves direct exposure of the mucosae to allergen and is indicated for patients who must document their reaction (eg, for occupational or disability claims) and sometimes for diagnosis of food allergy. For example, patients may be asked to exercise to diagnose exercise-induced asthma, or an ice cube may be placed on the skin for 4 min to diagnose cold-induced urticaria.
Ophthalmic testing has no advantage over skin testing and is rarely used.
Nasal and bronchial challenge are primarily research tools, but bronchial challenge is sometimes used when the clinical significance of a positive skin test is unclear or when no antigen extracts are available (eg, for occupation-related asthma).
Removal or avoidance of allergic triggers is the primary treatment for allergy, as well as the primary preventive strategy (see Prevention).
Antihistamines block receptors; they do not affect histamine production or metabolism. H1 blockers are a mainstay of treatment for allergic disorders. H2blockers are used primarily for gastric acid suppression and have limited usefulness for allergic reactions; they may be indicated as adjunctive therapy for certain atopic disorders, especially chronic urticaria.
Oral H1 blockers (see Table 1: Oral H Blockers) relieve symptoms in various atopic and allergic disorders (eg, seasonal hay fever, allergic rhinitis, conjunctivitis, urticaria, other dermatoses, minor reactions to blood transfusion incompatibilities); they are less effective for allergic bronchoconstriction and systemic vasodilation. Onset of action is usually 15 to 30 min, with peak effects in 1 h; duration of action is usually 3 to 6 h. Products that contain an oral H1 blocker and a sympathomimetic (eg, pseudoephedrine) are widely available OTC for use in adults and children ≥ 12 yr. These products are particularly useful when both an antihistamine and a nasal decongestant are needed; however, they are sometimes contraindicated (eg, if patients are taking an MAOI).
Oral H1 blockers are classified as sedating or nonsedating (better thought of as less sedating). Sedating antihistamines are widely available without prescription. All have significant sedative and anticholinergic properties; they pose particular problems for the elderly and for patients with glaucoma, benign prostatic hyperplasia, constipation, orthostatic hypotension, delirium, or dementia. Nonsedating (nonanticholinergic) antihistamines are preferred except when sedative effects may be therapeutic (eg, for nighttime relief of allergy, for short-term treatment of insomnia in adults or nausea in younger patients). Anticholinergic effects may also partially justify use of sedating antihistamines to relieve rhinorrhea in URIs.
Antihistamine solutions may be intranasal (azelastine or olopatadine to treat rhinitis) or ocular (azelastine, emedastine, ketotifen, levocabastine, olopatadine, or pemirolast to treat conjunctivitis). Topical diphenhydramine is available but should not be used; its efficacy is unproved, drug sensitization (ie, allergy) may occur, and anticholinergic toxicity can develop in young children who are simultaneously taking oral H1 blockers.
|PrintOpen table in new window
Mast cell stabilizers:
These drugs block the release of mediators from mast cells; they are used when other drugs (eg, antihistamines, topical corticosteroids) are ineffective or not well-tolerated. These drugs may be given orally (cromolyn), intranasally (eg, azelastine, cromolyn), or ocularly (eg, azelastine, cromolyn, lodoxamide, ketotifen, nedocromil, olopatadine, pemirolast). Several ocular and nasal drugs are dual-acting mast cell stabilizers/antihistamines (see above).
Corticosteroids can be given intranasally (see Table 2: Inhaled Nasal Corticosteroids and Mast Cell Stabilizers) or orally. Oral corticosteroids are indicated for allergic disorders that are severe but self-limited and not easily treated with topical corticosteroids (eg, acute asthma exacerbations, severe widespread contact dermatitis) and for disorders refractory to other measures. Ocular corticosteroids are used only when an ophthalmologist is involved because infection is a risk. NSAIDs are typically not useful, with the exception of topical ketorolac for allergic conjunctivitis.
|PrintOpen table in new window
Leukotriene modifiers are indicated for treatment of mild persistent asthma (see Drug therapy) and seasonal allergic rhinitis.
Anti-IgE antibody (omalizumab) is indicated for moderately persistent or severe asthma refractory to standard treatment (see Drug therapy). Some evidence suggests that omalizumab is efficacious as treatment for chronic urticaria refractory to antihistamine therapy.
Exposure to allergen in gradually increasing doses (hyposensitization or desensitization) via injection or in high doses sublingually can induce tolerance and is indicated when allergen exposure cannot be avoided and drug treatment is inadequate. Mechanism is unknown but may involve induction of IgG antibodies, which compete with IgE for allergen or block IgE from binding with mast cell IgE receptors; induction of interferon-γ, IL-12, and cytokines secreted by TH1 cells; or induction of regulatory T cells.
For full effect, injections must be given monthly. Dose typically starts at 0.1 to 1.0 biologically active units (BAU), depending on initial sensitivity, and is increased weekly or biweekly by ≤ 2 times with each injection until reaching the maximum tolerated dose (ie, the dose that begins to elicit moderate adverse effects); patients should be observed for about 30 min postinjection during dose escalation because anaphylaxis may occur after injection. The maximum tolerated dose should be given q 4 to 6 wk year-round; year-round treatment is better than preseasonal or coseasonal treatment, even for seasonal allergies.
Allergens used are those that typically cannot be avoided: pollens, house dust mites, molds, and venom of stinging insects. Insect venoms are standardized by weight; a typical starting dose is 0.01 mcg, and usual maintenance dose is 100 to 200 mcg. Animal dander desensitization is ordinarily limited to patients who cannot avoid exposure (eg, veterinarians, laboratory workers), but there is little evidence that it is useful. Desensitization for food allergens is under study. Desensitization for penicillin and certain other drugs and for foreign (xenogeneic) serum can be done (see Desensitization).
Adverse effects are most commonly related to overdose, occasionally via inadvertent IM or IV injection of a dose that is too high, and range from mild cough or sneezing to generalized urticaria, severe asthma, anaphylactic shock, and, rarely, death. Adverse effects can be prevented by the following:
Reducing the dose of pollen extract during pollen season is recommended. Epinephrine, O2, and resuscitation equipment should be immediately available for prompt treatment of anaphylaxis.
Allergic triggers should be removed or avoided. Strategies include the following:
Adjunctive nonallergenic triggers (eg, cigarette smoke, strong odors, irritating fumes, air pollution, cold temperatures, high humidity) should also be avoided or controlled when possible.
Last full review/revision March 2014 by Peter J. Delves, PhD
Content last modified March 2014