Traditional descriptions of type I hypersensitivity and its manifestations center on systemic immunoglobulin E (IgE)-mediated reactions to inciting antigens. Hence, many current diagnostic and therapeutic measures are based on systemic skin testing for allergy, systemic pharmacotherapy, and immunotherapy. Recent developments in rhinology and pulmonology, particularly in defining the phenomenon of local IgE production in various airway inflammatory conditions, have an impact on both medical and surgical diagnosis and management of these conditions. This review includes a discussion of allergy as a systemic disease, current systemic diagnostic and management strategies for allergy, and local IgE presence and synthesis in the upper and lower airways.
Allergy is a clinical manifestation of an exaggerated immune response following repeated exposures in a genetically predisposed “atopic” patient. In allergic patients, the body responds to usually harmless substances as though they were pathogens. Allergy may present as a variety of systemic conditions, most commonly hay fever, allergic rhinitis, asthma, and eczema. The symptoms of allergy are predictable when considered in context of chemical mediators released by mast cells during a type I immunoglobulin E (IgE)-mediated hypersensitivity reaction. Mast cells are concentrated in the submucosal layer of the respiratory tract, gastrointestinal tract, conjunctiva of the eye, and subcutaneous layer of the skin, which correlates directly to the target organs that manifest symptoms during an allergic reaction. Histamine and other mediators released from mast cells and basophils during allergic reactions contribute to vasodilation, glandular secretion, and increased vascular permeability.
It is estimated that 20% to 25% of the general population manifests clinical symptoms of allergy. A nationwide survey in 2006 showed that 54.6% of people in the United States tested positive to at least one allergen. The profound economic impact of allergy is increasing. Between 2000 and 2005, the cost of treating allergic rhinitis almost doubled from $6.1 to $11.2 billion, with more than half of this money spent on prescription medications. Costs related to lost productivity, missed work, and health care costs incurred by exacerbation of coexisting medical conditions by allergy are more difficult to quantify.
Immunology
A discussion of allergy and its treatment would be incomplete without an understanding of the effector cells involved. An IgE-mediated allergic reaction consists of 2 phases: early humoral reaction and a late cellular reaction. An almost immediate response to an allergen occurs with a preformed specific IgE molecule presenting an antigen to an attached mast cell. This antigen presentation results in degranulation and release of histamine from mast cells in the submucosal layer, with subsequent vasodilatation and increased vascular permeability. In addition to histamine, mast cells release a cascade of other proinflammatory mediators (prostaglandins, leukotrienes, platelet-activating factor, bradykinin, and cytokines) within minutes of the antigen-antibody reaction. The presence of cytokines and leukotrienes up-regulate or induce de novo expression of adhesion molecules, selectins, and integrins. This release of mediators inspires an influx of other inflammatory cells, primarily eosinophils, but also basophils and neutrophils into the reaction site within several hours following the humoral reaction. This cellular influx comprises the late or cellular reaction, and may enhance the allergic symptom expression for up to several days.
In a milieu of cytokines and other mediators, B lymphocytes proceed to generate further antigen-specific IgE that will be displayed on the B cells in preparation for subsequent exposures. The critical step in the commitment of B cells to synthesis of IgE is heavy chain class switching, which involves recombination within the immunoglobulin heavy chain gene cluster, thus changing the ε germ line gene into the rearranged gene. This gives rise to the ε mRNA for the ε heavy chain of IgE. Several signals are necessary for heavy chain switching, whether in vivo or in vitro. When provoked by allergen exposure, mast cells and Th2-type lymphocytes release interleukin (IL)-4 and IL-13. These signals target the ε gene for recombination by binding to CD40. CD40 ligand is constitutively expressed on mast cells and expressed after allergen activation on T cells. Cross-linking of CD40 on B-cell membrane induces the cell to undergo heavy chain switching. Immunoglobulin subclasses vary in abundance. The 4 IgG subclasses make up 75% of the immunoglobulins found in serum, with a concentration in healthy individuals of about 10 mg/mL. IgG responds to a wide range of antigens, including many bacterial proteins. In contrast, the least-abundant Ig in serum is IgE, with a normal concentration of approximately 150 ng/mL.
Traditional systemic allergy testing
Current diagnostic and treatment regimens for allergic patients revolve around systemic IgE. Diagnostic techniques are dependent on sufficiently detectable levels of systemic IgE, and treatment is administered for local and systemic symptom control with pharmaceutical agents or antigen-specific immunotherapy. Increased evidence for local IgE production and concomitant disease manifestations incurred by local inundation with IgE has abounded recently. Local IgE production and its effects have been hypothesized to explain the discrepancy between sensitization detected by systemic allergy testing and clinical expression of allergy. Despite research evidencing increased local tissue IgE levels, the development of routine testing for local IgE and treatment regimens centered on elevated local IgE have not been routinely used.
Systemic Skin Testing for Allergy
The gold standard for allergy testing is in vivo antigen-specific skin testing, which is essentially a semiquantitative measurement of the early-phase type I hypersensitivity reaction. Antigens are selected by the tester according to their likelihood to induce a reaction based on the patient’s medical history. These are applied to the skin by an epicutaneous screening method or an intracutaneous diluted fashion. If a sensitized mast cell to that specific antigen exists, a humoral reaction will ensue with development of a wheal and flare that reaches its maximum at about 20 minutes after exposure. The diameter of the early-phase wheal is measured and the exuberance of the allergy inferred. A late-phase cellular reaction may ensue, but this is not interpreted as part of standard testing. Therefore, despite manifestations of allergy typically occurring at local intranasal, ocular, or bronchial sites, gold standard allergy testing methods have traditionally been undertaken via systemic skin-testing protocols.
The most commonly used epicutaneous test is the prick or puncture method initially described by Lewis and Grant in 1924 and later modified by Pepys in 1975. A drop of purified antigen or control fluid is applied to the skin, and a needle or similar device is used to puncture the epidermis through the fluid without inciting bleeding. After allowing time for a humoral reaction to develop, based on presence or absence of antigen-specific IgE-sensitized mast cells in the skin, the resulting reaction is graded. More exuberant reactions develop in patients with higher levels of systemic antigen-specific IgE; however, negative prick tests do not preclude existence of allergen-specific IgE at lower levels that may still result in clinical allergy symptoms.
Intracutaneous or intradermal systemic allergy testing may complement prick testing, or be used alone to quantify systemic antigen-specific responses. Although the antigen concentration used in intradermal testing is far weaker than antigen concentration in prick testing, the volume of antigen to which the patient is exposed is much greater, increasing a risk of an anaphylactic reaction. The intradermal test was reported as an allergy skin testing method by Cooke in 1915. The 2 most common methods for intradermal testing are single-dilution and intradermal dilution testing, previously known as skin-endpoint titration. Intradermal dilution testing is more clinically relevant given the ability to accurately quantitate a patient’s sensitivity and infer the starting concentration for immunotherapy. Single-dilution testing provides only a positive or negative result, and all immunotherapy is begun at an extremely low dose to ensure safety, prolonging overall time of escalation dosing.
Systemic In Vitro Testing for Allergy
Systemic in vivo skin testing, despite remaining the gold standard, inherently presents several drawbacks. The degree of reactivity is suppressed by antihistamines, which must be avoided for at least 72 hours before testing. Patients often experience an increase in symptoms with withdrawal of antihistamine medications. Skin-testing methods have been refined to encompass exposure to very low doses or diluted antigen to maximize the safety profile; however, a small risk of anaphylactic reaction persists with in vivo testing. Rates of untoward reactions during skin testing, both large local reactions and systemic reactions, are reported at a rate of 0.02% to 1.40%. Protocols to manage these life-threatening reactions are mandated for administering centers to maximize success for management of anaphylaxis.
An alternative to in vivo testing exists for patients who are advised against or unlikely to be able to tolerate skin testing. Radioallergosorbent testing, or RAST testing, involves a radioimmunoassay capable of detecting specific IgE antibodies in serum. A solid phase is manufactured in which allergens react with serum drawn from a patient. Antigen-specific IgE binds to the solid phase antigens. This solid phase antigen-antibody complex is then incubated with radiolabeled rabbit antibodies to human IgE. The amount of antibody present is calculated by measurement of the radioactive marker. The modified RAST was introduced in 1979 by Fadal and Nalebuff to increase the sensitivity of the test while maintaining its specificity. Adjustments were made not only to the technical aspects of the testing procedure but also to the scoring and interpretation mechanisms. The modified RAST is more useful to the clinician as correlations to intradermal dilutional testing can be made to facilitate initiation of immunotherapy. Some advocate that total quantitative measurement of serum systemic IgE provides additional diagnostic value in addition to modified RAST. Even modified RAST, however, remains less sensitive than in vivo skin testing for allergy detection.
Traditional systemic allergy testing
Current diagnostic and treatment regimens for allergic patients revolve around systemic IgE. Diagnostic techniques are dependent on sufficiently detectable levels of systemic IgE, and treatment is administered for local and systemic symptom control with pharmaceutical agents or antigen-specific immunotherapy. Increased evidence for local IgE production and concomitant disease manifestations incurred by local inundation with IgE has abounded recently. Local IgE production and its effects have been hypothesized to explain the discrepancy between sensitization detected by systemic allergy testing and clinical expression of allergy. Despite research evidencing increased local tissue IgE levels, the development of routine testing for local IgE and treatment regimens centered on elevated local IgE have not been routinely used.
Systemic Skin Testing for Allergy
The gold standard for allergy testing is in vivo antigen-specific skin testing, which is essentially a semiquantitative measurement of the early-phase type I hypersensitivity reaction. Antigens are selected by the tester according to their likelihood to induce a reaction based on the patient’s medical history. These are applied to the skin by an epicutaneous screening method or an intracutaneous diluted fashion. If a sensitized mast cell to that specific antigen exists, a humoral reaction will ensue with development of a wheal and flare that reaches its maximum at about 20 minutes after exposure. The diameter of the early-phase wheal is measured and the exuberance of the allergy inferred. A late-phase cellular reaction may ensue, but this is not interpreted as part of standard testing. Therefore, despite manifestations of allergy typically occurring at local intranasal, ocular, or bronchial sites, gold standard allergy testing methods have traditionally been undertaken via systemic skin-testing protocols.
The most commonly used epicutaneous test is the prick or puncture method initially described by Lewis and Grant in 1924 and later modified by Pepys in 1975. A drop of purified antigen or control fluid is applied to the skin, and a needle or similar device is used to puncture the epidermis through the fluid without inciting bleeding. After allowing time for a humoral reaction to develop, based on presence or absence of antigen-specific IgE-sensitized mast cells in the skin, the resulting reaction is graded. More exuberant reactions develop in patients with higher levels of systemic antigen-specific IgE; however, negative prick tests do not preclude existence of allergen-specific IgE at lower levels that may still result in clinical allergy symptoms.
Intracutaneous or intradermal systemic allergy testing may complement prick testing, or be used alone to quantify systemic antigen-specific responses. Although the antigen concentration used in intradermal testing is far weaker than antigen concentration in prick testing, the volume of antigen to which the patient is exposed is much greater, increasing a risk of an anaphylactic reaction. The intradermal test was reported as an allergy skin testing method by Cooke in 1915. The 2 most common methods for intradermal testing are single-dilution and intradermal dilution testing, previously known as skin-endpoint titration. Intradermal dilution testing is more clinically relevant given the ability to accurately quantitate a patient’s sensitivity and infer the starting concentration for immunotherapy. Single-dilution testing provides only a positive or negative result, and all immunotherapy is begun at an extremely low dose to ensure safety, prolonging overall time of escalation dosing.
Systemic In Vitro Testing for Allergy
Systemic in vivo skin testing, despite remaining the gold standard, inherently presents several drawbacks. The degree of reactivity is suppressed by antihistamines, which must be avoided for at least 72 hours before testing. Patients often experience an increase in symptoms with withdrawal of antihistamine medications. Skin-testing methods have been refined to encompass exposure to very low doses or diluted antigen to maximize the safety profile; however, a small risk of anaphylactic reaction persists with in vivo testing. Rates of untoward reactions during skin testing, both large local reactions and systemic reactions, are reported at a rate of 0.02% to 1.40%. Protocols to manage these life-threatening reactions are mandated for administering centers to maximize success for management of anaphylaxis.
An alternative to in vivo testing exists for patients who are advised against or unlikely to be able to tolerate skin testing. Radioallergosorbent testing, or RAST testing, involves a radioimmunoassay capable of detecting specific IgE antibodies in serum. A solid phase is manufactured in which allergens react with serum drawn from a patient. Antigen-specific IgE binds to the solid phase antigens. This solid phase antigen-antibody complex is then incubated with radiolabeled rabbit antibodies to human IgE. The amount of antibody present is calculated by measurement of the radioactive marker. The modified RAST was introduced in 1979 by Fadal and Nalebuff to increase the sensitivity of the test while maintaining its specificity. Adjustments were made not only to the technical aspects of the testing procedure but also to the scoring and interpretation mechanisms. The modified RAST is more useful to the clinician as correlations to intradermal dilutional testing can be made to facilitate initiation of immunotherapy. Some advocate that total quantitative measurement of serum systemic IgE provides additional diagnostic value in addition to modified RAST. Even modified RAST, however, remains less sensitive than in vivo skin testing for allergy detection.
Treatment of allergy
Management options for allergy consist of avoidance measures and several classes of pharmacotherapeutic agents, but the only “cure” for this disorder requires immunotherapy. A tailored regimen, largely designed by trial and error, can be designed for the patient with the goal of symptom control, from antihistamines, decongestants, mast cell stabilizers, corticosteroids, anticholinergics, and leukotriene modifiers. Unsatisfactory relief with these mechanisms prompts consideration of immunotherapy.
Avoidance
The best and most effective management of allergy is avoidance of allergens when possible. Patient education can be provided by verbal counseling as well as administration of printed materials with specific control regimens for various antigens, such as dust mites, molds, and animal dander. Antigens are not always avoidable, and even when immunotherapy is instituted, overwhelming exposure to antigens both during treatment and following therapy may continue to provoke symptoms. As such, pharmacotherapeutic management of symptoms is a cornerstone in treating the allergic patient.
Pharmacotherapy
Antihistamines help to control symptoms of sneezing and rhinorrhea, symptoms induced by vasodilation, increased vascular permeability, and increased glandular production that occurs with direct effects of histamine. First-generation antihistamines, or “sedating” antihistamines, compete with histamine for H1 receptor sites on target organs ( Table 1 ). Second-generation, or “nonsedating,” antihistamines do not cross the blood-brain barrier, and as such, have a better tolerated side-effect profile. Topical, intranasal antihistamines are now available and offer benefits of antihistamine and anti-inflammatory actions. Third-generation antihistamines seek to offer equal or superior potency with further-enhanced safety profile and longer duration of action.
| Drug Class | Example | Mechanism of Action | Current Indication | |
|---|---|---|---|---|
| Oral antihistamine | 1st generation | Diphenhydramine | Blocks H1 receptor sites on target organs | Allergic rhinitis |
| 2nd | Loratadine | |||
| 3rd | Desloratadine | |||
| Topical antihistamine | Azelastine | Blocks H1 receptor site | Allergic rhinitis | |
| Topical decongestant | Neosynephrine | Alpha-adrenergic agonist | Acute nasal congestion | |
| Oral decongestant | Phenylephrine | Alpha-adrenergic agonist | Nasal congestion | |
| Oral steroid | Prednisone | Decreases capillary permeability, stabilizes lysosomal membranes, blocks action of migratory inhibitory factor, inhibits phospholipase | Late-phase allergic reactions | |
| Intranasal steroid | Mometasone | See above | Chronic allergic rhinitis | |
| Leukotriene modifier | Monteleukast | Inhibits formation of leukotrienes | Asthma, nasal polyposis, allergic rhinitis | |
| Chromones | Sodium cromoglycate | Mast cell stabilizer | Before allergen exposure | |
| Topical anticholinergic | Ipratropium bromide | Blocks muscarinic receptors (M2 and M3) | Allergic rhinitis with prominent rhinorrhea, Asthma | |
| Sympathomimetic | Epinephrine | α and β adrenergic receptor activation | Anaphylaxis | |
| Inhaled short-acting selective beta2-adrenergic agonists | Albuterol | Directly activates β2-receptors | Bronchospasm | |
| Inhaled long-acting selective β2 agonist | Salmeterol | Directly activates β2-receptors | Asthma, COPD | |
| Methylxanthine | Theophylline | Nonselective phosphodiesterase inhibitor, ↑ apoptosis of inflammatory cells, ↑ histone deacetylase activity | Asthma | |
| Anti-IgE antibodies | Omalizumab | Prevents IgE binding to mast cells | Asthma | |
Decongestants are alpha-adrenergic agonists that oppose vasodilation and decrease symptoms of nasal congestion. Systemic administration carries a risk profile characterized by the vasopressive actions, mainly exacerbation of hypertension. They readily cross the blood-brain barrier, and can cause central nervous system stimulation. When applied topically to the nose, systemic effects are minimized, but risk of rebound rhinitis and cycles of addiction can ensue.
Mast cell stabilizers have multiple actions, but retain their original description in name. They are used topically intranasally, and are most effective when administered before allergen exposure to prevent an allergic reaction. They have a short half-life and must be redosed multiple times daily. Advantages include a very limited side-effect profile.
Corticosteroids are anti-inflammatory agents that are primarily effective for the late-phase allergic reaction. They do not prevent allergic reaction, but diminish the effects by mitigating effector cells and enzymes. Systemically administered, this class of medication has a side-effect profile list that is quite lengthy, often increased as dose and duration of treatment are increased. They can result in suppression of endogenous steroid production, central nervous system stimulation, gastrointestinal upset, exacerbation of hypertension and diabetes, and skeletal and tendon injury. Topical nasal or inhaled corticosteroids are a heavily relied upon class of agents for allergy and asthma symptom management, as they are the most potent nasal therapy and they diminish the need for systemic administration. Topical administration results in very low systemic absorption, and has usually few side effects locally, including nasal crusting, epistaxis, hoarseness, oral candidiasis, and drying of the mucous membranes.
Anticholinergics were originally used systemically to counteract rhinorrhea present in allergy. They were poorly tolerated given the excessive mucosal drying effects, with nasal crusting and thickened mucous. Intranasal anticholinergics are effective at controlling rhinorrhea with very little systemic absorption and, therefore, limited side effects.
Leukotriene modifiers were designed to modulate development of allergic reaction by inhibiting development of leukotrienes or barring their effects. They were originally solely used for asthma and nasal polyposis, but have recently gained approval from the Food and Drug Administration for a role in treatment of allergic rhinitis as well.
Immunotherapy
Systemic immunotherapy is offered to patients whose symptoms are not well controlled by simple pharmacotherapeutic measures, symptoms that are severe and prolonged, allergies to antigens that are not readily avoidable, and to patients who are capable of complying with the prolonged treatment time. Standard antigen-specific immunotherapy was developed in 1911 by Leonard Noon. It entails injecting escalating doses of antigen until a maintenance dose is achieved, and then continuing injection treatments until the patient has been completely asymptomatic for perennial allergens for 1 to 5 years and seasonal allergens for 2 to 3 seasons. Injections are usually administered once weekly with increasing dose and potency of antigen until desired effects are noted, continued for a total of 1 year, and then maintenance doses are continued every 2 to 3 weeks for a total duration of 3 to 5 years. Patients are monitored in the treatment environment following each injection in the unlikely event that systemic reaction ensues. Multiple studies have been performed detailing efficacy of this regimen for treatment of multiple allergens in curing the patient of allergic symptoms with lasting efficacy after treatment has ceased.
Alternative routes for administering immunotherapy have been explored and developed with the goal of creating a system of treatment that can be safely administered by the patient at home, decreasing cost and increasing convenience, while maintaining comparable results. Additional benefits that have been hypothesized are directly treating the reactive sites, namely airway mucosa. Oral administration of antigen concentrates was originally investigated in the 1920s; however, further pursuit was abandoned because of the perception of suboptimal efficacy. An adaptation of oral immunotherapy is sublingual immunotherapy (SLIT), where the allergen extract is held under the tongue for 2 to 3 minutes before swallowing. Major investigations for this regimen have been pursued in Europe, and results from several studies demonstrate similar long-term results of symptom improvement with treatment for both seasonal and perennial allergens when compared with subcutaneous immunotherapy.
The concept of intranasal and intrabronchial immunotherapy has been suggested for many years. Initial trials from Europe revealed efficacy in local symptom control without development of a systemic effect, measured by a total decrease in serum IgE. Further investigation has been abandoned given the superior efficacy and better tolerated side-effect profile of SLIT.
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