Consensus Guidelines on Practical Issues of Immunotherapy-Canadian Society of Allergy and Clinical Immunology (CSACI)

The early phase of the immediate hypersensitivity reaction results from the release of mediators from mast cells or basophils, the key effector cells in the allergic reaction. High-affinity receptors on mast cells and basophils bind immunoglobulin E (IgE). When a multivalent allergen binds its specific IgE, the high-affinity receptors are cross-linked, leading to a cascade of events that result in mast cell and basophil degranulation. The resulting mediators and growth factors are also associated with the late-phase allergic response and with chronic inflammation. Eosinophils and neutrophils are attracted by chemotactic factors to the site of an immediate hypersensitivity reaction; in chronic allergic reactions, mononuclear cell infiltrates are also found. The inflammatory response has features of cellular and humoral immunity, and it results from a network of interacting soluble mediators, cytokines, and chemokines [7].

Randomized double-blind placebo-controlled (RDBPC) studies have shown that immunotherapy is effective for the treatment of allergic rhinitis, allergic asthma, and hypersensitivity to insect stings [8]. The efficacy of subcutaneous specific immunotherapy has been documented in RDBPC studies of allergic rhinitis (and usually conjunctivitis) induced by birch, grass, ragweed, and Parietaria pollens; house dust mite; cat; and Alternaria[2]. The beneficial effects of immunotherapy on asthma have been shown in regard to grass and ragweed pollen, house dust mites, cat, Cladosporium, and Alternaria[6, 9]. Venom immunotherapy has proven to be an effective treatment for individuals at risk of anaphylaxis from yellowjacket, wasp, honeybee, white-faced hornet, and yellow hornet stings. Recently, fire ant whole-body extract has become available for immunotherapy [10]. Latex, peanut, and cockroach allergens are under investigation [11–13].

Once signs and symptoms consistent with an allergic disease have been identified, a skin test demonstrating allergen-specific IgE antibodies is the primary means of confirming the presence of specific sensitization [14]. Prick/puncture and intradermal/intracutaneous skin tests provide a biologically relevant demonstration of an immediate hypersensitivity response in the skin. Awheal and/or flare reaction denotes a positive test.

In the prick test, a drop of allergen is placed onto the epidermis. The usual sites are on the volar surface of the lower arm and back. The prick/puncture is made with a single-point, multipoint, or bifurcated needle. Excess allergen is blotted off with tissue or gauze. The immediate wheal and flare reaction for the allergen tested is read within 15 minutes, the time to maximum wheal diameter. Individual test sites need to be far enough apart (2-3 cm) so that results do not over-lap. Dermatographism can lead to a false-positive reaction; this emphasizes the importance of including a negative control. Medications with antihistaminic effects (such as antihistamines and tricyclic antidepressants) may cause a false-negative result; thus, a positive control (usually histamine) is necessary.

Allergen may also be administered intradermally with a 26- to 27-gauge needle; 0.01 to 0.05 mL are injected, and the results are read after 15 minutes. Minor changes in the volume of extract injected have a minimal effect on the diameter of the wheal and on erythema. Intradermal skin tests may be more affected by the actual concentration of antigen and therefore require significantly less antigen than a skin-prick test requires [15]. Higher intradermal concentrations are associated with false-positive results; hence, skin-prick tests are considered to be more specific, with the exception of skin tests for insect venom and for penicillin [16].

Arbitrary grading schemes for wheal and erythema size are often used. However, measurement of the wheal and erythema in millimetres is more consistent and is recommended [17].

Allergy testing is considered a safe procedure, but anaphylaxis may occur rarely in highly sensitive patients. Emergency equipment and appropriate medications must be available for the treatment of potentially life-threatening reactions. An allergic reaction resulting from skin testing in a patient who is on β-blockers and possibly on angiotensin-converting enzyme inhibitors may be more enhanced and less responsive to treatment.

The use of different skin-prick test devices may affect the interpretation of the skin-prick test [18]. Results obtained with a single needle, a bifurcated needle, or Morrow-Brown devices may not be exactly the same. The actual amount delivered into the skin varies between 0.42 and 0.82 nL and appears to be more dependent on characteristics of the patient's skin than on the device or on the skill of the operator. When performed by a trained individual, skin tests are highly reproducible. Studies comparing different devices are in progress [18, 19]. (All biologic testing has associated hazards, and appropriate precautions are suggested. Disposable testing devices are recommended.)

Allergen-specific IgE antibody may also be detected in the blood by a radioallergosorbent test (RAST). "Second-generation" RAST-type assays such as the Pharmacia ImmunoCAP system provide more quantitative, sensitive, and precise serum IgE antibody results.

The Phadebas RAST (Pharmacia, Sweden) was the first assay to report in vitro detection of specific IgE antibodies. The newer Pharmacia ImmunoCAP system uses a different matrix to bind the IgE with various monoclonal and polyclonal anti-IgE-detection antibodies. Nonisotopic labels have increased the shelf life of reagents, making assays simpler and free of radioisotopes. The newer assays produce a more quantitative and reproducible measurement than the earlier paper disk-based RAST produced. RAST and other in vitro assays may be less sensitive diagnostically than skin tests but may be helpful in certain clinical situations such as those requiring tests for food and venom [20].

Specific immunotherapy (SIT) involves the subcutaneous administration of an increasing adequate dose of the specific allergen as a treatment of allergy [22]. Its first use was in 1911, when Noon treated "pollinosis" by injecting small amounts of pollen extract under the skin of individuals who had hay fever [23]. The technique's clinical efficacy (as determined by symptoms, medication scores, early- and late-phase skin responses, and allergen thresholds) has been demonstrated [24]. The aim of SIT is to inhibit the IgE immune response directed toward the allergen while leaving the remainder of the immune response intact. Unlike many other allergy treatments, SIT targets the underlying cause of the condition. Currently, there are four main explanations for the mechanism of immunotherapy: (1) immune deviation from T helper 2 cell (Th2) to T helper 1 cell (Th1) response, (2) production of immunoglobulin G (IgG)-blocking antibodies, (3) reduction in mast cells and eosinophils, and (4) production of regulatory T cells and cytokines.

The allergic reaction may reflect a Th2 response characterized by the production of IgE and the proallergenic cytokines interleukin (IL)-4 and IL-5. Studies indicate that SIT induces a switch from a Th2 response toward a Th1 response, with a reduction in IL-4 and IL-5, an increase in IL-10, and the induction of interferon-γ-secreting cells [22, 24–31]. SIT affects cytokine production, but how it does this and how the alteration of cytokine production relates to clinical outcome remain to be determined.

The mechanism of SIT has also been explained by a shift in antibody production away from IgE and toward IgG. SIT causes an initial slight increase and then a mild decrease in allergen-specific IgE levels and blunts the seasonal rise in IgE [24]. There is, however, a large increase in allergen-specific IgG, especially IgG4. This observation has led to the "blocking antibody" theory, in which the IgG competes with IgE for allergen binding. This prevents the allergen from cross-linking IgE and causing the activation of mast cells, basophils, or other IgE receptor-expressing cells [24]. However, IgG4 production increases in all patients who receive SIT, regardless of their clinical response to SIT [24]. Also, in rush SIT, the treatment is effective before IgG levels increase [32]. Although IgG may play a role, the mechanism is more complex than the simple competition of IgG with IgE.

A more comprehensive explanation of the role of IgG as a blocking antibody may involve serum IgE-facilitated allergen presentation (S-FAP) [33, 34]. The concept that allergen-specific IgE may facilitate T-cell activation comes from the observation that when IgE is incubated with its specific allergen and then mixed with CD23-expressing antigen-presenting cells (APCs), the minimal concentration of allergen required for T-cell activation is reduced at least 1,000-fold [35]. It is thought that the IgE allergen complexes are bound by Fcε receptors on APCs, leading to endocytosis, processing, major histocompatibility complex class II antigen presentation, and (ultimately) greater CD4⁺ T-cell activation [35, 36]. The increase in allergen-specific IgG (IgG4) following SIT prevents the formation of allergen IgE complexes that would normally bind to Fcε receptors, therefore preventing S-FAP [33, 37]. Indeed, IgG-containing fractions of sera from patients receiving SIT (and not those from controls) have been shown to inhibit S-FAP of Bet v 1 [33, 34]. The reduction in S-FAP has also been shown to reduce IL-4, IL-5, and IFN-γ production of Bet v 1- specific T cells [34]. Therefore, in addition to the blocking-antibody concept of IgG, the role of IgG in SIT and in the treatment of allergy may also be the result of the abrogation of S-FAP (leading to increased allergen threshold levels) and reduced late-phase reactions.

SIT has also been shown to reduce the number of mast cells and eosinophils. The number of metachromatic cells (a marker for mast cells) has been shown to be reduced in individuals responding to SIT [24]. In a placebo-controlled human trial with grass pollen, it was shown that the number of mast cells after SIT was correlated with clinical response (seasonal symptoms) and the use of rescue medication [38]. The reduction of mast cells lowered the immediate response to allergen and was associated with a reduction in IL-4, IL-5, and IgE and with the recruitment and activation of eosinophils. Whether reduced owing to lowered mast cell activity or through other mechanisms, eosinophil levels have also been shown to drop after SIT [24].

SIT has also been shown to cause the induction of T-regulatory cells, specifically IL-10⁺ CD25⁺ CD4⁺ and CD8⁺ regulatory T cells. These cells are known for their regulatory function in many diseases (especially autoimmune diseases) and for the production of IL-10 and transforming growth factor beta (TGF-β), two regulatory cytokines. There is evidence that SIT induces the production of both CD25⁺ CD4⁺ T cells and regulatory CD8⁺ T cells, leading to immune tolerance and to the production of IL-10, an immunoregulatory cytokine [24]. Immunotherapy has been shown to cause local increases in cells positive for IL-10 messenger ribonucleic acid in nasal mucosa after 2 years of treatment [37]. IL-10 reduces the levels of IL-4 and IgE synthesis. It also plays a role in class-switching to IgG4, leading to a decreased ratio of IgE to IgG and an increased ability of IgG antibodies to block IgE [37]. Although support for the production of IL-10 and TGF-β exists, other studies have not found a change in IL-10 or TGF-β levels. This may suggest a state of anergy, rather than active suppression [24]. The production of regulatory T cells, however, is strongly implicated in SIT.

The exact mechanism of SIT has not been completely characterized. However, evidence supports the role of an immunologic skew from Th2 to Th1, the production of IgG-blocking antibodies, a decrease in mast cells and eosinophils, decreased early- and late-phase allergic responses, and the proliferation of regulatory T cells and cytokines. It is important to note that these events are highly integrated and that SIT results in a complex response rather than a straightforward mechanism.

SIT is highly effective in selected patients with IgE-mediated disease and sensitivity to one allergen or a limited number of allergens. It is the only antigen-specific immunomodulatory treatment in routine use. It has been shown to provide long-term benefit and is the only currently available treatment that modifies the natural history of allergic disease for at least several years after discontinuation [39].

The efficacy and safety of SIT might be improved by novel strategies that directly target the T-cell response. These include genetically modified non-IgE-binding recombinant allergens, allergen-derived peptides, and novel Th1-promoting adjuvants derived from bacteria, such as monophosphoryl lipid and immunostimulatory sequences. Results of further controlled trials are awaited [39].

SIT is effective for perennial and seasonal allergic rhinitis, allergic asthma, and hypersensitivity to insects of the order Hymenoptera, including the fire ant [1]. The clinical efficacy of SIT for allergic rhinitis and asthma, as determined by using potent and standardized extracts in carefully selected patients, is well documented [5, 40, 41]. Candidates for SIT include patients with symptoms induced by allergens, patients with sensitivity to a single allergen or a few allergens, and young patients without chronic irreversible changes in upper airways [3]. The beneficial effects of SIT are limited to the specific allergens that are administered. There may be some effect in decreasing hypersensitivity to allergens whose antigens cross-react with the allergen administered. Improvement is dose dependent, and most available studies indicate that 4 to 12 μg of the major determinant of allergen are usually required for an effective maintenance dose [4].

Efficacy has been documented in the majority of well-designed RDBPC trials on the treatment of rhinitis caused by grass, ragweed, Parietaria, and mountain cedar. RDBPC studies have also shown that pollen SIT reduces respiratory symptoms and/or decreases asthma medication requirements in asthmatic patients with pollen sensitivity [3]. There is some evidence that early allergen SIT may prevent the acquisition of new allergic sensitivities [42]. There is much less information available with respect to mixtures of pollen extracts. Some older studies showed that treatment with multiple allergens may be successful, but this area requires further study [43].

SIT with house dust mite (Dermatophagoides pteronyssinus and/or Dermatophagoides farinae) allergen has been shown to reduce symptoms and the need for asthma medications in patients with house dust mite allergy, as well as to inhibit the late-phase response and to increase the threshold dose required to elicit bronchial obstruction in allergen inhalation challenge studies. Numerous studies with house dust mite have demonstrated the effectiveness of SIT in decreasing the symptoms of perennial allergic rhinitis [3, 5, 44].

SIT with cat allergen has led to improvement in bronchial sensitivity in patients with cat-allergic asthma. SIT with dog dander may be less effective than SIT with cat dander because of significant variations between different breeds of dogs and because of the choice of allergens included in the therapeutic extract [45].

SIT with fungal vaccines is problematic owing to the biologic variability within fungal species and the increased variability of the material available for vaccine formulation. Also, the patterns of exposure to fungal species are less appreciated [46]. Two RDBPC studies have demonstrated that SIT with Cladosporium and Alternaria vaccines may be effective for rhinitis and asthma [3, 5, 47]. Proteolytic enzymes in some fungal extracts may digest allergens in the pollen vaccines.

Immunotherapy for peanut, latex, and cockroach allergies is still experimental [10, 12, 42, 4].

SIT vaccines are individually prepared for each patient. The clinical efficacy of the vaccine correlates with the choice of allergen, method of allergen mixing, dose selection, method of administration, and other factors. When a qualified physician prescribes allergen SIT, all of these matters must be addressed in a clearly documented prescription (examples appear in previously published guidelines) [8].

The dose build-up schedule should be included with each SIT prescription. Clear instructions should be provided to the administering physicians and nurses. Informed consent should be obtained from the patient before SIT is started [3].

Allergic and nonallergic reactions from SIT may be local and systemic [50]. Large local reactions may occur with aqueous immunotherapy. Subcutaneous nodules from alum-adsorbed vaccine occur rarely. The incidence of adverse reactions has been reported to be up to 1.9% in SIT whereas the adverse reaction rate may be as high as 36% in rush protocols. Allergic and anaphylactic reactions may result from SIT [51]. Fatalities have been rarely reported in some studies [51–59].

Other adverse reactions have included immune complex reactions, serum sickness, brachial plexus neuropathy, pemphigus vulgaris, and nonorganic reactions, but causality has not been definitely established in all cases. Collagen vascular and lymphoproliferative diseases are not caused by SIT but theoretically can be exacerbated after SIT [51–59].

Anaphylaxis may be secondary to errors in dosage, the presence of symptomatic asthma, a high degree of hypersensitivity, accelerated or rush administration schedules, or injections given during periods of potential seasonal exacerbations of asthma or rhinitis. Precautions to minimize adverse reactions during SIT include the avoidance of β-blockers, a 30-minute observation period after injection, written and/or verbal guidelines to patients and health care professionals, the presence of a physician during the injection, and optimal treatment of systemic reactions. Standard forms and standardized allergen preparation and dispensing procedures are recommended [3, 51, 56–59]. Fatalities after SIT can be reduced by strictly following practice guidelines on patient selection, postinjection observation, preinjection screening of asthmatic patients, and early treatment of anaphylaxis [60].

The recommended equipment in settings where allergen SIT is administered includes stethoscopes and sphygmomanometers, tourniquets, syringes, hypodermic needles, large-bore needles, and set-ups for intravenous-fluid administration and oral airways. The recommended therapeutic agents include aqueous epinephrine hydrochloride (1:1,000) for intramuscular administration, oxygen, intravenous fluids, antihistamines, and corticosteroids. Intubation equipment and vasopressors for injection may be considered in selected clinical settings [51, 59].

The prompt recognition of systemic reactions and the immediate use of epinephrine are the mainstays of therapy.

Skin testing is valid for detecting allergen-specific IgE in young children. Young children may be at increased risk for systemic reactions from SIT. In young children, psychological problems or adverse reactions may result from SIT [3, 5, 41, 61]. Studies have suggested that SIT may reduce the development of asthma in children who have seasonal rhinoconjunctivitis [3, 62–65]. The development of new unrelated sensitization in children may be inhibited by SIT treatment with a single allergen [3, 66, 67].

Understanding of the allergic immune response has led to ongoing research and the development of novel forms of immunotherapy [87, 88].

Traditional subcutaneous SIT has been shown to be efficacious but not to be without potentially life-threatening complications [39, 60]. Novel forms of immunotherapy for allergic disorders have therefore been sought to improve the risk-benefit ratio. These forms have involved modification of the allergen and the investigation of noninjectable routes [39, 89–97].

Local nasal immunotherapy, local bronchial immunotherapy, oral immunotherapy, and sublingual immunotherapy have recently been developed as immunotherapy using newer delivery routes [89–93]. Anti-IgE therapy is now available in Canada, the United States, and other parts of the world [94–97]. Novel strategies for immunotherapy include recombinant genetically modified allergen proteins, allergen-derived peptides, smaller peptide vaccines, novel adjuvants, and immunostimulatory sequences of deoxyribonucleic acid containing CpG [20, 95, 96].

Sublingual-swallow SIT has been shown to be safe and efficacious for allergy to many pollens and allergy to house dust mites [98–115]. One study comparing subcutaneous SIT with sublingual SIT in birch allergy patients showed similar efficacy in each [113]. Most RDBPC trials of sublingual SIT have confirmed a clinical efficacy ranging from a 20 to 50% reduction in symptom or medication scores, a superiority to placebo, and an efficacy approaching or equal to that of subcutaneous SIT [93, 95, 113]. The efficacy of sublingual SIT starting as late as 2 to 3 weeks before the ragweed season has been demonstrated [99]. Sublingual SIT for house dust mite allergy and asthma has been shown to maintain clinical efficacy 4 to 5 years after discontinuation, similar to the long-standing effects of subcutaneous SIT for grass [101]. Adverse events seem to be fewer than with subcutaneous SIT; oral and gastrointestinal irritations are the predominant ones and are mostly mild to moderate in severity. Severe events have not been reported [93, 100]. The optimum dose, the frequency of administration, the number of seasons or length of time to be administered, and the mixing of antigens all need further clarification and study. Current effective doses range from 20 to 400 times the doses usually required in subcutaneous SIT [95, 98–114]. Sublingual SIT has come to be more frequently prescribed in Europe. The global cost savings to the health care system and patients' acceptance of risk versus benefit and cost versus benefit require ongoing study.

As a professional society, the CSACI has a responsibility (to its members and to the physicians and patients for whom it provides consultations and ongoing care) to develop guidelines for the safety and quality assurance of allergen SIT. The prescription and preparation of allergen SIT must follow accepted standards of practice. Treatment sets prepared in the allergist's facility must conform to recommended good manufacturing practices. The development of standardized forms, as recently recommended by other professional allergy societies, is suggested [3]. Also, in conjunction with provincial and federal regulatory bodies, the CSACI should continue to recommend that the prescription and preparation of allergen SIT be undertaken by physicians with the appropriate expertise and qualifications [1, 3, 4, 116, 117].

The Royal College Specialty Committee in Clinical Immunology and Allergy recognizes that specific immunotherapy (SIT) is a skill that is unique to our specialty. The objectives for our training programs as well as our final in-training evaluation reports have recently been revised to incorporate SIT as a key technical and expert skill required of our trainees. Residents in our program must know the immunologic mechanisms of immunotherapy and its indications. They should be able to prescribe and adjust SIT treatment programs for patients with environmental and venom allergies.

SIT began as the only allergy treatment modality for physicians practicing almost 100 years ago, before pharmacologic therapy was available. It has remained a key component of allergy management since then. Scientific advances in recent years have helped to explain the mechanisms of action and to identify the relevant antigens and the allergic epitopes for determining the effectiveness of SIT. Treatment plans and the adjustment of dosage depending on the patient's conditions have become more uniform, and standardized antigens have improved the effectiveness of SIT.

All trainees in Royal College programs approved by the Canadian Society of Clinical Immunology and Allergy should have the knowledge to administer SIT to patients as an appropriate and effective treatment.

Dr. Donald Stark, Chair, Specialty Committee on Clinical Immunology and Allergy, Royal College of Physicians and Surgeons of Canada, Specialty Training Committee in Clinical Immunology and Allergy Recommendations on Immunotherapy