Background
Allergen immunotherapy can provide significant improvements in allergic symptoms and reduce the need for additional pharmacotherapy. Allergen immunotherapy has been clinically demonstrated to provide long-term clinical benefits, including symptomatic disease remission and a reduction in allergic disease progression from rhinitis to asthma. [1]
The first report describing immunotherapy was published in 1911, when Noon described that the subcutaneous injection of a pollen extract suppressed allergen-induced symptoms. Since then, allergen immunotherapy has been used in medical practice to successfully treat hypersensitivity to many allergens, including dust mites, grass, ragweed and tree pollen, insect venom, and animal dander. Allergen immunotherapy is appropriate for patients suffering from immunoglobulin E (IgE)–mediated allergic diseases such as seasonal allergic rhinitis, perennial rhinitis, allergic asthma, and insect venomanaphylaxis.
Aside from allergen immunotherapy, the other available treatment options for allergic diseases include aeroallergen avoidance and pharmacotherapy. In addition, surgery may be offered as an adjunct in appropriate patients (eg, septoplasty for nasal septal deviation, sinus surgery for chronic sinusitis, turbinate reduction for turbinate hypertrophy, nasal polypectomy for nasal polyps).
Effective treatment reduces symptoms and medication utilization while improving quality of life. Allergen immunotherapy has demonstrated long-term effectiveness in symptom reduction more than 3 years following treatment cessation and has prevented the development of new sensitizations in children.
Allergic pathophysiology and method of action
Within seconds to minutes of allergen exposure, mast cells initiate granule exocytosis, releasing preformed histamine, serine proteases, and proteoglycans. These series of cellular events give rise to immediate allergic symptoms that peak within 15-30 minutes and affect the skin, eyes, and both upper and lower respiratory systems. Mast cells also synthesize prostaglandins and leukotrienes and release additional proinflammatory mediators and cytokines, which increase vascular permeability and promote recruitment of other effector cells.
A second, or late phase, of allergic inflammation can occur approximately 6-12 hours after allergen exposure. This late allergic response is the result of activated CD4+ T cells, eosinophils, neutrophils, and basophils leaving the bloodstream and infiltrating the local tissue upon allergen exposure. Each of these cell types contains important mediators in the allergic response: Basophils have histamine-containing granules; eosinophils contain major basic protein and leukotrienes, particularly leukotriene C4; and neutrophils produce lipids, cytokines, and proteases that directly damage tissues, including mucosal membranes, and further augment mast cell and eosinophil activity. [2, 3, 4, 5, 6, 7, 8]
Allergen immunotherapy suppresses the allergen-induced late response and diminishes the immediate phase via prevention of allergen-driven Th2 responses, including reductions in levels of interleukin (IL)–4, IL-13, IL-5, and IL-9. Perhaps more importantly, the decrease in Th2 response is complemented by a change in the immune response to one favoring the “protective” Th1 pathways. Allergen immunotherapy induces IL-10 and transforming growth factor (TGF)-β–secreting T regulatory cells, which appear to suppress Th2 responses. Additionally, IL-10 contributes to the switching of immunoglobulin isotypes to IgG4, and TGFβ mediates switching to IgA.
The down-regulation of the allergic response in a patient undergoing allergen immunotherapy is attributed to increases in IgG1, IgG4, and IgA, and also a decrease in IgE. This alteration is affiliated with significant reductions in the numbers of infiltrating T cells, basophils, eosinophils, and neutrophils. IgG4 antibodies also block allergen-induced IgE-dependent histamine released by basophils. Allergen immunotherapy results in a long-term reduction in serum allergen-specific IgE levels. Significant reductions in the early-phase response have also been demonstrated. [9, 10, 11, 8, 12]
Sublingual immunotherapy
Sublingual immunotherapy experienced renewed interest in England after a review of safety and protocols of subcutaneous immunotherapy identified a 0.5%-5.6% rate of systemic reactions and fatalities, most commonly due to "preventable errors." These findings reduced the use of subcutaneous immunotherapy in Britain and encouraged research into allergy treatment with sublingual immunotherapy. Most of the data address monotherapy, and research has yet to delineate ideal dosing concentrations, dosing schedules, dosing duration, and duration of patient response.
In sublingual immunotherapy, the theory is that the antigen comes into contact with Langerhans-like dendritic cells residing in the oral mucosa on the floor of the mouth under the tongue. These cells capture the antigen and migrate to local lymph nodes, resulting in the production of blocking antibodies and induction of T-regulator cells, which then suppress Th-1 and Th-2 cellular response via IL-10 and TGFβ mechanisms, both of which are described in detail above. [13, 14]
Sublingual immunotherapy has been demonstrated to decrease allergen-specific IgE, bronchial reactivity, and nasal and conjunctival eosinophils and neutrophils and to increase IgG4, IL-10, TGFβ, and interferon (INF)–gamma. Significant long-lasting symptom control of allergic rhinitis, rhinoconjunctivitis, and asthma has been demonstrated in multiple studies. This method is very convenient for patients, decreases blood and latex exposure, and is believed to be quite safe , although several cases of anaphylaxis have been reported in the literature. [15, 16, 17, 18, 19, 20, 21]
Indications
Allergen immunotherapy is appropriate for patients with IgE-mediated allergic diseases such as seasonal allergic rhinitis, perennial rhinitis, allergic asthma, and insect venomanaphylaxis whose symptoms are not well controlled with avoidance measures and pharmacotherapy and in whom an IgE-mediated reaction to antigen has been documented. Some recent reports have suggested that immunotherapy may also aid in atopic dermatitis. [22, 23, 24, 25, 26, 27, 28]
Contraindications
Sublingual immunotherapy is contraindicated in severe asthma. In addition, there are no data available for simultaneous treatment of multiple sensitivity. It is recommended that subcutaneous immunotherapy not be given to patients with uncontrolled asthma. [29]
Technical Considerations
Best Practices
The treating physician should be familiar with allergy testing and immunotherapy, along with its risks. The physician must be equipped to expeditiously address any allergic emergency.
History
A detailed allergy history is very important to obtain when embarking on a treatment regimen in a patient who presents with allergic symptoms. The allergy history may be complex and may require several patient encounters to allow for completeness.
Examples of questions to ask for delineation of symptoms include the following:
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Symptomatic involvement of eyes, ears, nose, sinuses, lungs, or skin
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Presenting symptoms (date of onset, fluctuation, timing/seasonality, severity, aggravating and relieving factors)
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Potentially etiologic exposures
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Chronic versus acute
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Indoor versus outdoor
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Past treatment attempts (over-the-counter and prescription medications)
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Past allergy testing
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Past immunotherapy
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Any changes in lifestyle (work, leisure, diet)
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Presence of asthma and the level of disease control
A list of additional medications (eg, beta-blockers, antidepressants) should be obtained, as well as any allergies to medications or adverse reactions to aspirin.
Complication Prevention
While adverse systemic reactions are uncommon, immunotherapy should be administered by only trained personnel, and resuscitative medications and equipment should be immediately available.
Adequate equipment and medications should be immediately available in case of anaphylaxis. The following are suggested equipment and medications for the management of systemic immunotherapy reactions. Modifications of this suggested list might be based on anticipated emergency medical services’ response time and physician’s airway management skills. [29]
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Stethoscope and sphygmomanometer
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Tourniquet, syringes, hypodermic needles, and intravenous catheters (eg, 14-18 gauge)
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Aqueous epinephrine HCL 1:1,000 weight/volume
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Equipment to administer oxygen by mask
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Intravenous fluid setup
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Antihistamine for injection (second-line agents for anaphylaxis, but H1 and H2 antihistamines work better together than either one alone)
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Corticosteroids for intramuscular or intravenous injection (second-line agents for anaphylaxis)
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Equipment to maintain an airway appropriate for the supervising physician’s expertise and skill
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Glucagon kit available for patients receiving beta-blockers
For more information, see the article Anaphylaxis.
Outcomes
With appropriate evaluation and management of allergy, including avoidance, environmental control, pharmacotherapy, and immunotherapy, the long-term results of allergy treatment are very positive. Many patients enjoy the benefits of long-lasting symptom control and improvement in quality of life.
Allergen immunotherapy has been clinically demonstrated to provide long-term clinical benefits, including symptomatic disease remission and a reduction in allergic disease progression from rhinitis to asthma. [1] A meta-analysis by Farraia et al showed a strong effect of allergen immunotherapy in preventing the onset of asthma in children who completed 3 years of treatment and in monosensitized patients. [30] Allergen immunotherapy has also demonstrated long-term effectiveness in symptom reduction more than 3 years following treatment cessation and has prevented the development of new sensitizations in children.
Allergen immunotherapy results in a long-term reduction in serum allergen-specific IgE levels. Significant reductions in the early-phase response have also been demonstrated. [9, 10, 11, 8, 12]
Research is ongoing regarding the comparative efficacy of sublingual immunotherapy with that of subcutaneous immunotherapy.
Local nasal immunotherapy (LNIT) is being investigated as an alternative noninjection method of immunotherapy for allergic rhinitis. A meta-analysis by Kasemsuk et al found that LNIT improved clinical symptoms, reduced medication use, and increased the nasal provocation threshold. [31]
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This image demonstrates the ideal location for administration of SCIT.
