Medications for Allergy

Allergic diseases have increased in prevalence over the last 20 years, affecting as many as 40 to 50 million people in the United States. Allergen immunotherapy has been a therapeutic option for more than 100 years, and its use is supported by multiple placebo-controlled trials. Allergen immunotherapy alters the course of allergic diseases through a series of injections of a mixture of extracts composed of clinically relevant allergens. The World Health Organization has replaced the term allergen extract with allergen vaccine to reflect that allergen vaccines are used in medicine as immune modifiers.

Indications

Allergen immunotherapy is used in the treatment of allergic rhinitis, allergic asthma, and stinging insect venom hypersensitivity. The diagnosis of these diseases is made by history and physical examination supported by testing to confirm IgE sensitization. Skin testing by prick or intradermal method is the preferred objective assessment, but in vitro tests such as the radioallergosorbent test are an alternative, especially when skin testing is unable to be performed.

Candidates for venom or Hymenoptera immunotherapy include all patients who have experienced life-threatening allergic reactions or non-life-threatening systemic reactions to Hymenoptera stings. The risk of ana-phylaxis for a venom-allergy patient from an insect sting is greater than the risk of anaphylaxis from immunotherapy. In patients younger than 16 years with only urticaria to Hymenoptera stings, immunotherapy is not generally recommended. However, in patients older than 16 years with only cutaneous reactions, immunotherapy is a recommended option. Venom immunotherapy is not indicated for patients who have only had local reactions at the stinging site, even large local reactions.

Immunotherapy is also effective for pollen, mold, animal dander, dust mite, and cockroach allergies. Symptomatic patients with allergic rhinitis and asthma despite allergen avoidance and pharmacotherapy are candidates for immunotherapy. Other candidates include allergic rhinitis or asthma patients having undesirable adverse reactions to medications, or those wishing to reduce or eliminate long-term pharmacotherapy. In addition to reducing symptoms to current allergens, immunotherapy may prevent the development of sensitization to new allergens or progression of allergic rhinitis to asthma, especially in children.

Mechanism

The exact mechanism of how immunotherapy works is not fully understood, but it involves shifting a patient’s immune response to allergen from a predominantly allergic T-lymphocyte (TH2) response to a “nonallergic” T-lymphocyte (TH1) response. Lymphocytes of a TH2 phenotype typically produce IL-4 and IL-5, cytokines needed for IgE production and eosinophil survival. Findings of increased production of IFN-y and a decreased production of IL-4 and IL-5 have not, however, been consistently demonstrated after immunotherapy. What has been consistent is the increased production of allergen-specific IL-10. IL-10 causes a shift in allergen-specific IgE to allergen-specific IgG4. This change may be orchestrated by regulatory T cells that downregulate allergic immune responses in part through the release of IL-10 and T-cell growth factor alpha (TGF-a). With allergen immunotherapy, the seasonal increase in allergen-specific IgE is blunted while protective allergen-specific IgG4 production is increased. However, these changes in IgE and IgG may not correlate with clinical efficacy, so periodic skin testing or in vitro IgE antibody measurements are not always useful in evaluating responses to immunotherapy.

Contraindications

Relative contraindications for immunotherapy include medical conditions that reduce patients’ ability to survive a serious systemic allergic reaction, such as coronary artery disease or the concurrent use of P-blockers (including   eye   drops)   or   angiotensin-converting   enzyme inhibitors.

Table. Immunotherapy

b-Adrenergic blocking agents may make the treatment of immunotherapy-related systemic reactions more difficult. Despite this, immunotherapy is indicated for patients with life-threatening stinging insect hypersensitivity receiving b-blockers. Allergen immunotherapy should not be initiated in asthmatic patients unless the patient’s asthma is relatively stable with pharmacotherapy. Patients who are mentally or physically unable to communicate clearly, such as very young children, are not good candidates for immunotherapy because it may be difficult for them to report early symptoms of a systemic reaction. Pregnancy is not a contraindication for immunotherapy, but by custom immunotherapy is not initiated during pregnancy. If a patient becomes pregnant while already on immunotherapy, the dose is not increased during the pregnancy but maintained at the current level in an attempt to avoid anaphylactic reactions.

Dosing

Safety

The greatest concern with immunotherapy is safety. Local reactions at the injection site, such as redness, swelling, and warmth, are common. These reactions can be lessened with HI antagonists prior to injections. Local reactions can be managed with treatments such as cold compresses or topical corticosteroids. Large local, delayed reactions (25 mm or larger) do not appear to be predictors of developing severe systemic reactions, and generally they do not require adjustment of dosing schedules. However, some patients with a greater frequency of large local reactions (more than 10% of injections) may be at increased risk for future systemic reactions, and dosing adjustments may be necessary.

The incidence of systemic reactions, such as urticaria, angioedema, increased respiratory symptoms (nasal, pulmonary, ocular), or hypotension, ranges from 0.05% to 3.2% per injection, or 0.84% to 46.7% of patients. Risk factors for systemic reactions include errors in dosing, symptomatic asthma, a high degree of allergen hypersensitivity, concomitant use of P-blocker medications, injections from a new vial, and injections given during periods when allergic symptoms are active, especially during the allergy season. A recent survey of 1700 allergists reported that 58% of responders had an event in which a patient received an injection meant for another patient, and 74% reported that patients had received an incorrect amount of vaccine. These errors resulted in a multitude of adverse events, including local reactions, systemic reactions, and even one fatality. Thus it is extremely important to make sure patients are questioned about potential risk factors and the correct vials are used to administer immunotherapy injections.

It is unclear if premedication with antihistamines can reduce the frequency of systemic reactions in conventional immunotherapy, but in cluster or rush immunotherapy, premedication can reduce the rate of systemic reactions.

The incidence of fatalities due to immunotherapy has not changed much over the last 30 years in the United States. From 1990 to 2001, fatal reactions occurred at a rate of 1 per 2.5 million injections, with an average of 3.4 deaths per year. Most fatal reactions occurred with maintenance doses of immunotherapy. The patient population at greatest risk was poorly controlled asthmatics. In many of the fatalities, there was either a substantial delay in giving epinephrine or epinephrine was not administered at all. The incidence of near-fatal reactions (respiratory compromise, hypotension, or both, requiring epinephrine) is 2.5 times more frequent than fatal reactions.

Treatment of anaphylaxis

Systemic allergic reactions can be life threatening and need to be treated rapidly. Most systemic reactions are limited to the skin, such as urticaria. Respiratory symptoms are seen alone or with skin manifestations in 42% of systemic reactions. Epinephrine is the standard of care for severe systemic or anaphylactic reactions. Treatment of anaphylactic reactions includes placing a tourniquet above the injection sites and immediately injecting epinephrine 1:1000 intramuscularly. For adults, the dose is typically 0.2 to 0.5 mL, and for children, 0.01 mL/kg (maximum, 0.3 mg dose) every 5 to 10 minutes as needed. For convenience, subcutaneous injection at the arm (deltoid) is frequently used, but intramuscular injection into the anterolateral thigh produces higher and more rapid peak levels of epinephrine.

Immunotherapy in general practice

Efficacy and outcomes

Once maintenance dosing is achieved for venom immunotherapy, 80% to 98% of individuals will be protected from systemic symptoms upon sting challenges. Maintenance therapy is generally recommended for 3 to 5 years, with growing evidence that 5 years of treatment provides more lasting benefit. A low risk of systemic reactions to stings (approximately 10%) appears to remain for many years after discontinuing venom immunotherapy. In children who have received venom immunotherapy, the chance of systemic reaction to a sting after discontinuation of immunotherapy is even lower.

The efficacy of immunotherapy for allergic rhinitis has been clearly demonstrated in a number of clinical trials. These studies have shown significant improvements in symptoms, quality of life, medication use, and immunologic parameters. Allergen immunotherapy for allergic rhinitis is also beneficial for at least 3 to 6 years after completion of a 3-year course of treatment.

The efficacy of immunotherapy for asthma has been assessed in many trials, but some studies have been difficult to interpret either because of the use of poor quality allergen extracts or suboptimal study design. The risk/benefit ratio of immunotherapy for asthma must always be considered. Currently, professional societies recommend that patients with asthma and forced expiratory volume in 1 second (FEVj) values less than 70% should not receive immunotherapy. A Cochrane review in 2004 examined the role of allergen immunotherapy for asthma. This review of 75 trials with 3100 patients found a significant reduction in asthma symptoms and medication use, and an improvement in bronchial hyperreactivity associated with the administration of allergen-specific immunotherapy. The reviewers concluded that immunotherapy is effective in asthma, and commented that one trial found that the size of the benefit was possibly comparable to inhaled corticosteroids.

Evidence-based medicine

This study evaluates the use of immunotherapy versus placebo in 206 children, 6 to 14 years of age, with only allergic rhinitis. The children were treated for 3 years with grass and/or birch extract depending on their sensitivities. After 3 years of immunotherapy, 19 patients developed asthma; 60 did not. In the placebo arm, 32 children developed asthma over 3 years, whereas 40 did not. The odds ratio for developing asthma in those receiving placebo was 2.5 times greater than that for children treated with allergen immunotherapy. This study was the first to demonstrate clearly that allergy immunotherapy may prevent or delay the onset of asthma in children with allergic rhinitis.

This study by Golden and colleagues evaluated the long-term outcomes of venom immunotherapy in 512 sensitized children. The mean follow-up was 18 years with a mean duration of immunotherapy of 3.5 years. The rate of systemic reactions after being restung was significantly greater among patients not treated with immunotherapy (17%) compared to those treated with venom immunotherapy (3%). In those treated with immunotherapy who only had skin manifestations prior to therapy, none had systemic reactions when restung.

Conclusion

Allergen immunotherapy has been a valuable tool in treating allergic rhinitis, asthma, and stinging insect hypersensitivity for decades. Although newer pharmaco-logic agents continue to become available, immunotherapy is still the only available treatment that alters the natural course of allergic diseases. Even though there are some risks, these can be minimized when immunotherapy is given in an appropriate environment to carefully selected patients. Recent guidelines have been established to further reduce the risks by establishing a universal system of reporting dilutions and establishing appropriate dosing. Despite a large body of evidence demonstrating the positive therapeutic benefits of immunotherapy, only 3 million patients in the United States are receiving immunotherapy out of a potential 40 to 50 million allergic patients, many of whom could benefit from this therapy. Newer therapies, such as anti-IgE (omalizumab), when used with immunotherapy, may improve the efficacy and safety profile of immunotherapy in the future. In addition, newer forms of immunotherapy such as T-cell peptides or immunostimulating sequences of DNA containing CpG motifs combined with allergens are currently under investigation.

Standard allergen immunotherapy is administered as a subcutaneous injection. The allergist selects the appropriate allergen extracts (vaccines) based on the patient’s clinical history, allergen exposure history, and the results of tests for allergen-specific IgE antibodies. The immunotherapy vaccine should contain only clinically relevant allergens. When preparing mixtures of allergen vaccines, the prescribing physician must take into account the cross-reactivity of allergens, the optimal dose of each constituent, and the potential for allergen degradation caused by proteolytic enzymes in the mixture. The efficacy of immunotherapy depends on achieving an optimal therapeutic dose of each allergen in the vaccine.

Allergen immunotherapy dosing consists of two treatment phases: the buildup phase and the maintenance phase. The prescribing physician must specify the starting immunotherapy dose, the target maintenance dose, and the immunotherapy buildup schedule. The highest concentration of vaccine projected to provide the thera-peutically effective dose is called the “maintenance” dose or concentrate. In general, the starting immunotherapy dose is 1000- to 10,000-fold less than the maintenance dose. For highly sensitive patients, the starting dose may be even lower. Dilute concentrations are more sensitive to degradation and lose potency more rapidly than the more concentrated preparations. Thus their expiration dates are much shorter and must be closely monitored.

The buildup phase involves injections with increasing amounts of allergens. The frequency of the injections can vary depending on the protocol. The most common or “conventional” protocol recommends dosing once to twice a week with at least 2 days between injections. It is customary to repeat or reduce the dose if there has been a substantial time interval between injections. Patients with greater sensitivity may require a slower buildup phase to prevent systemic reactions. With this schedule, maintenance is usually achieved after 3 to 6 months. Alternative schedules such as “rush” or “cluster” immunotherapy rapidly achieve maintenance dosing and should only be administered by an allergist/immunologist because of an increased risk for systemic reactions. Immunotherapy dosing schedules should be written by trained allergists/immunologists, and primary care physicians should seek their advice if questions or issues arise during administration.

The maintenance phase begins when the effective therapeutic dose is achieved. This final dose is based on several factors, including the specific allergen, the concentration of the extract, and how sensitive a patient is to the extract. Once maintenance is achieved, the intervals for injections range from every 2 to 6 weeks but are individualized for each patient. Clinical improvement can be demonstrated shortly after the patient reaches his or her maintenance dose. If no improvement is noted after 1 year of maintenance therapy, a reassessment should be done.

Table. Conventional immunotherapy.

Table. Typical buildup schedule for conventional immunotherapy.

Possible reasons for lack of efficacy need to be evaluated, and if none are found, discontinuation of immunotherapy should be considered. Patients should be evaluated at least every 6 to 12 months while on immunotherapy by the prescribing allergist/ immunologist. Duration of maintenance therapy is generally 3 to 5 years. Treatment may lead to prolonged clinical remission and persistent alterations in immuno-logic reactivity. The severity of disease, benefits from sustained treatment, and the convenience of treatment are all factors that are considered when deciding the length of therapy for each individual patient.

Many studies, especially from Europe, have shown that high-dose sublingual allergen immunotherapy is effective for certain patients, but this mode of therapy is not approved by the U.S. Food and Drug Administration and is considered investigational. Many questions still  remain   unanswered   on   sublingual

immunotherapy including effective dose concentrations, schedule for buildup and maintenance therapy, and timing of dosing (i.e., seasonal or continuous throughout the year). Additionally, sublingual therapy requires much larger doses of allergen, anywhere from 10 to 300 times greater, making cost an issue. Finally, the utility of sublingual immunotherapy for polysensitized patients is not yet determined.

Immunotherapy should be administered in a setting that permits the prompt recognition and management of adverse reactions. The preferred setting is the prescribing physician’s office, especially for high-risk patients. However, patients may receive immunotherapy injections at another health care facility if the physician and staff at that location are equipped to recognize and manage systemic reactions, in particular anaphylaxis. Because of the potential for anaphylaxis, immunotherapy should not be administered at home. Informed consent should be obtained prior to administering immunotherapy. A full, clear, and detailed documentation of the patient’s immunotherapy schedule must accompany the patient when receiving injections at another health care facility. Use of a constant uniform labeling system for dilutions may reduce errors in administration. The maintenance concentration and serial dilutions should be prepared and labeled for each individual patient.

A brief review of a patient’s current health status is recommended prior to dosing. It is important to assess any current asthma symptoms, increased allergic symptoms, any new medications, or any delayed reactions to the previous injection. In patients with asthma, peak expiratory flow rate measurements should be obtained prior to each injection.  In general, immunotherapy injections should be withheld if the patient presents with an acute asthma exacerbation or if peak flow measurements are below 20% of the patient’s baseline values. Immunotherapy may need to be decreased or held if significant allergic symptoms are present prior to an injection.

Table. Immunotherapy vaccine labeling.

Most severe reactions develop within 20 to 30 minutes after the immunotherapy injection, but reactions can occur after this time. Patients need to wait at the physician’s office for at least 20 to 30 minutes after the immunotherapy injection. In some cases, the wait may need to be longer depending on the patient’s history of previous reactions.

It is usual practice to reduce the dose of vaccine when the interval between injections is longer than prescribed. This reduction in dose should be clearly stated on the patient’s immunotherapy schedule. Because of the potential of extract degradation over time, when new vials are started the initial dose is decreased and then built back up to maintenance. When a systemic reaction occurs, the physician needs to decide if immunotherapy should be continued. This should be done in consultation with the allergist/immunologist who prescribed the immunotherapy. If the decision is to continue, the dose of the vaccine needs to be appropriately reduced to lessen the risk of a subsequent systemic reaction.

Allergen immunotherapy is appropriate and effective treatment in patients who have symptoms of allergic rhinitis and/or allergic asthma with natural exposure to allergens and who demonstrate specific immunoglobulin E antibodies (by skin tests or in vitro tests) to relevant allergens. Allergen immunotherapy is medically indicated in patients with respiratory allergies when symptoms are not controlled adequately by pharmacotherapy and avoidance measures, or when there is a need to avoid adverse effects of pharmacotherapy or a wish to reduce long term use of pharmacotherapy. Randomized, double-blind, placebo-controlled studies show that immunotherapy is effective for the treatment of allergic rhinitis and/or asthma. In patients with moderate to severe respiratory allergies, immunotherapy should be considered.

Allergen immunotherapy, a series of allergen vaccine injections over a defined period, results in decreased sensitivity or tolerance to inhaled or injected allergens, which can be measured both clinically and immunologically. Vaccine is used to describe the immune-modifying properties of allergen immunotherapy. Such therapy is used to treat allergic rhinitis (hay fever), allergic asthma, and stinging-insect hypersensitivity. During the first half of the 20th century, efficacy of allergen immunotherapy was based primarily on clinical observations. However, over the past 40 yr, scientific investigations of numerous allergens and of the complexities of the allergic reaction have revealed the immunological changes required for successful immunotherapy.

When to Consider Allergen Immunotherapy

•   Individuals with documented appropriate clinical symptoms, and either skin test or in vitro evidence of immunoglobulin E-allergen-specific antibody.

•   Allergic manifestations of rhinitis, bronchial asthma, or stinging insect venom sensitivity.

•   Failure to respond to elimination or control of environmental allergic factors.

•   Failure to respond to symptomatic medication or difficulty/inconvenience of using these medications regularly.

Allergens

Sources of aeroallergens include, but are not limited to, pollen, molds, and animal emanations, such as dander, saliva, urine, feces, and other animal parts derived from mammals, birds, insects, and house dust mites. Aeroallergens are able to induce a specific immunoglobulin (immunoglobulin)E antibody response. This requires that the aeroallergen is sufficiently abundant in the ambient air to both sensitize and provoke allergic symptoms in an atopic individual.

Ragweed pollen-induced allergic rhinitis is an excellent model for the study of aeroallergen-induced allergic diseases: (1) the pollen is found in the air in sufficient quantities during the predictable fall pollinating season, and ragweed pollen proteins are potent sensitizers; (2) ragweed pollen induces symptoms in the sensitized patient during and immediately following the ragweed pollinating season; and (3) ragweed-induced allergic rhinitis can be diagnosed easily historically and by appropriate in vivo or in vitro testing for specific immunoglobulin E to ragweed allergens and by provocative challenges.

The immediate effects of allergen exposure are readily observed in the ragweed-allergic patient during the ragweed pollinating season. So too are symptoms in the sensitized patient caused by indoor exposure to allergens such as those derived from dust mites, cat, and dog, although patients may suffer with perennial allergic symptoms from such environmental exposures. Such a temporal relationship is evidence for specific allergen sensitivity; however, allergic symptoms also are caused by various overlapping pollen and mold seasons. Therefore, it is sometimes difficult to ascertain which particular allergens are the most important as a cause of allergic disease. The physician must know which pollen, molds, and other aeroallergens are most important in a given geographical area in which the patient lives. The American Academy of Allergy Asthma and Immunology has established a North American Pollen Network. Pollen and mold reports in various geographical areas are available by contacting the online service www.pollen.com, or by obtaining patient information from the American Academy of Allergy Asthma and Immunology, 611 East Wells Street, Milwaukee, Wisconsin 53202-3889 (www.AAAAI.org).

Allergen vaccines

Licensing of allergen vaccines for clinical use in the United States is regulated by the US Food and Drug Administration, Center for Biologies Evaluation and Research, Division of Allergenic Products and Parasitology. Many of the common vaccines used in clinical allergy practice are available as standardized products or are pending standardization. This means that allergen vaccines, as provided by commercial manufacturers, meet standards that assure that the appropriate allergens are included in a given vaccine. However, many allergen vaccines derived from natural sources are not yet standardized, and it is probably not economically feasible or practical to standardize all of those currently available for diagnosis and treatment. Currently, unstandardized allergenic vaccines are labeled on the basis of relative concentration (weight by volume or protein nitrogen units per milliliter) of the respective allergen source.

Indications for allergen immunotherapy

Allergen avoidance, pharmacotherapy, and patient education form the basis for treating allergic rhinitis, conjunctivitis, and asthma. Allergen immunotherapy is indicated for patients with these diseases who have demonstrated evidence of specific immunoglobulin E antibodies to clinically relevant allergens and in whom environmental control and pharmacotherapy have failed. The absolute indication for prescribing allergen immunotherapy depends on the degree to which symptoms can be reduced by allergen avoidance, by medication and the amount, type, and length of time medications are required to control symptoms. Immunotherapy, when appropriate, should be used adjunctively with continued environmental control measures and appropriate pharmacotherapy. For stinging-insect-induced anaphylaxis, specific Hymenoptera venom immunotherapy is the treatment of choice.

Controlled clinical studies demonstrate that allergen immunotherapy is effective for patients with respiratory allergies. Immunotherapy is specific for the allergen administered, and the content of the treatment vaccine is based on the patient’s history and allergy test results. In general, the very young (<5 yr old) and elderly patients (>65 yr old) are not candidates for immunotherapy. The very young patient with respiratory allergic diseases usually responds favorably to environmental control and pharmacotherapy, and an uncooperative child is not the ideal candidate for allergen injections. Theoretically, the young patient may benefit the most by immunotherapy by altering the natural course of a chronic disease. The elderly patient rarely requires immunotherapy for the management of rhinitis and/or asthma. The optimal duration of immunotherapy to achieve the best therapeutic response remains unknown; however, studies indicate that 3-5 yr of immunotherapy is adequate for patients who have had a good therapeutic response.

Table Summary of Controlled Trials of Immunotherapy

- No effect

+ Positive effect

+ + Strong positive effect

Immunological changes induced by allergen immunotherapy

The commonly recognized immunological changes that occur secondary to successful allergen immunotherapy include: (1) a rise in serum IgG-”blocking” antibody; (2) blunting of the usual seasonal rise of immunoglobulin E followed by a slow decline of immunoglobulin E over the course of immunotherapy; (3) increase in IgG- and IgA-blocking antibodies in the respiratory secretions; (4) reduction in basophil reactivity and sensitivity to specific allergens; (5) reduced production of inflammatory mediators during both early- and late-phase responses to allergen exposure; (6) decreased mast cell numbers and eosinophil recruitment; and (7) reduced lymphocyte responsiveness (proliferation and cytokine production) to specific allergens and a shift of T-cell subsets away from a TH2 type (producing IL-4 and IL-5) in favor of a THl-type T-lymphocyte response (interferon [IFN-y]).

The hallmark of asthma and allergic rhinitis is allergic inflammation of the mucosa and submucosa, predominantly caused by eosinophils. TH2 lymphocytes amplify and prolong allergic inflammation and late-phase reactions. TH1 cytokines, i.e., IFN-y and IL-2, inhibit production of TH₂ cytokines. Successful immunotherapy is associated with a shift in IL-4/IFN-y production (from IL-4 to IFN-y) either as a consequence of downregulation of the TH₂ response or increase in the THj response by regulatory T cells screting interleukin (IL)-IO and transforming growth factor (TGF)-p.

Not all immunological changes associated with effective immunotherapy occur in all subjects, although there is general correlation between clinical improvement and favorable alterations from baseline immunological parameters. Reduction in biological sensitivity to specific allergens has been demonstrated in allergen immunotherapy trials to such allergens as ragweed, mixed grasses, birch and mountain cedar pollen vaccines; the molds, Alternaria spp and Cladosporium spp; and cat dander and house dust mites. Successful allergen immunotherapy ameliorates, but usually does not completely eliminate, the respiratory symptoms of allergic rhinitis and allergic asthma.

Clinical trials and scientific studies

Reasons for lack of benefit from immunotherapy

The reasons for lack of benefit from allergen immunotherapy include: (1) inappropriate treatment with such therapy of non-immunoglobulin E-mediated disease, such as chronic nonallergic rhinitis orvasomotor rhinitis; (2) utilization of low-potency allergen vaccines; (3) administration of inadequate doses of allergen; (4) ineffective environmental control resulting in continued excessive exposure, for example, to cat or dog dander; (5) a coexistent medical problem, such as sinusitis and nasal polyps, which accounts for most of the symptoms; (6) the allergen vaccine lacks important allergens because of undiagnosed or unrecognized sensitivities.

Overview of practical aspects

Specific allergen immunotherapy is effective treatment for specific patients with allergic rhinitis and allergic asthma. Careful selection of the patient and the relevant allergen(s) for immunotherapy requires expertise and knowledge about the pathophysiology of allergic diseases and regional outdoor and indoor allergen sources. Allergen immunotherapy is indicated for symptomatic patients in whom an adequate trial of environmental control and avoidance and appropriate pharmacotherapy has failed. Reduction of symptoms and the amount of medications required occurs in patients who received optimal maintenance doses of specific immunotherapy for a 3- to 5-yr period.

Local Reactions to Allergen Immunotherapy

•   Redness and swelling (usually dime-quarter sized) are not uncommon and easily managed with an ice pack, with or without an antihistamine.

•   Larger reactions may require an antihistamine as well as short term oral corticosteroids.

•   Significant local reactions may require adjustment of subsequent allergen immunotherapy doses.

Duration of immunotherapy

Clinical trials and observations indicate that immunotherapy can be stopped after 3-5 yr of successful therapy. The results of grass, tree and ragweed immunotherapy trials demonstrate efficacy for several years after cessation of such therapy. In one ragweed study, the immunological parameters and nasal lavage mediators remained unchanged 1 yr after the treatment vaccine was stopped. House dust mite immunotherapy administered for 1-6 yr and then discontinued was found to be most effective after discontinuation if it had been administered for at least 3 yr. The effect of immunotherapy on the reduction of the skin test end points at the conclusion of the treatment was correlated with the duration of efficacy after immunotherapy cessation. Efficacy of a 3-yr course of animal dander immunotherapy was assessed 5 yr after its discontinuation, and one-third of these subjects continued to demonstrate tolerance to cat exposure. When relapses occur after the immunotherapy is discontinued, a good response to restarting such therapy occurs more rapidly than occurs during the initial course of immunotherapy.

Adverse reactions

Precautions

No allergen vaccine should be considered completely safe for an allergic subject, and immunotherapy should be carried out only by trained personnel who know how to administer immunotherapy injections, to adjust doses, and to manage adverse reactions in a setting where appropriate equipment for such management is immediately available. A detailed protocol to adjust for missed injections and for reactions to immunotherapy is necessary. A protocol for the management of anaphylaxis is indicated, and personnel who administer injections should be trained in the appropriate treatment of anaphylaxis. Prompt recognition and immediate administration of epinephrine in systemic reactions are the mainstays of therapy.

Patients at higher risk for severe life-threatening systemic reaction include those with:

1.  Unstable or symptomatic asthma.

2.  Significant seasonal exacerbation of their allergic symptoms, particularly asthma.

3.  A high degree of hypersensitivity (by skin testing or specific immunoglobulin E measurements).

4.  Accelerated schedules of immunotherapy, particularly during the initial build-up period.

5.  High-dose maintenance regimens in highly sensitive allergic patients.

6.  Concomitant use of P-blockers (which makes treatment of anaphylaxis more difficult with epinephrine). p -Blockers should be discontinued, when possible, prior to initiation of immunotherapy.

7.  Injections from new vials.

Patients who become pregnant while already receiving immunotherapy may be maintained at their current or a reduced dose during pregnancy. Immunotherapy should not be started during pregnancy unless a life-threatening situation exists, e.g., Hymenoptera hypersensitivity. Relative contraindications for immunotherapy include: (1) serious immunopathological and immunodeficiency diseases; (2) malignant disease; (3) severe psychological disorders; (4) poor compliance; (5) patients who are noncompliant; (6) severe uncontrolled asthma or irreversible airway obstruction, <70% predicted FEV1; (7) significant cardiovascular diseases, which increase the potential side effects from epinephrine; (8) children under 5 yr of age; and (9) systemic mastocytosis.

The risk of systemic allergic reactions and fatal reactions should be reduced and, it is hoped, eliminated by (1) avoiding errors in dosing; (2) utilizing preventive protocols to minimize risk, such as measuring peak flow rates in patients with unstable asthma; (3) reducing doses when injections are given from new vials; (4) reducing doses when injections are given during a particularly high pollen- or mold-induced seasonal exacerbation; and (5) by using standardized allergen vaccines.

Any physician who administers immunotherapy, regardless of specialty, should be present when the injections are given. The patient should be required to wait 30 min following the injection. A longer wait is indicated for high-risk patients. In the event of any adverse reactions or uncertainity about the dose, the allergist should be consulted prior to administration of another dose of allergen vaccine.

Treatment of allergic reactions: medications and equipment

Physicians prescribing and/or administering such therapy must be aware of the potential risks and institute appropriate clinic procedures to minimize them. Prompt recognition of signs and symptoms of a systemic reaction and immediate use of epinephrine (subcutaneously or preferably intramuscularly) to treat such a reaction are the mainstays of therapy. The following equipment, medications, and reagents should be available: (1) stethoscope and sphygmomanometer, (2) tourniquets, syringes, hypodermic needles, and large-bore (14-gage) needles, (3) aqueous epinephrine HC1,1;1000 w/v, (4) equipment to administer oxygen,(5) equipment to administer intravenous fluids, (6) oral airway, (7) antihistamine,(8) corticosteroids, and (9) injectable vasopressor. The rare situation in which invasive procedures (electrical cardioversion, tracheotomy, intracardiac injection of drugs) might be essential does not justify the risk of their being available for use under less than ideal circumstances. It is impractical to insist that these procedures be available in every clinic situation.

Future trends in immunotherapy

New technology and advancement of knowledge in the basic mechanisms and pathophysiology of allergic diseases will completely change allergen immunotherapy in the future. These advances should result in new, safer, and substantially more effective methods of manipulating the human immune response. Several approaches may be used: (1) novel delivery systems, such as sublingual immunotherapy (the World Health Organization accepts this type of immunotherapy as a valid alternative to the subcutaneous route for allergic rhinitis and asthma); (2) allergen fragments or peptides (devoid of anaphylactic potential) for active immunotherapy; (3) immunoglobulin E-binding haptens of major allergens for passive saturation of effector cells and induction of blocking antibodies; (4) plasmid DNA immunization; (5) allergen-specific antibodies and antibody fragments for passive therapy, i.e., to be used by inhalation into the nose or lungs; and (6) immuno-therapy with humanized anti-immunoglobulin E monoclonal antibody (Xolair™), which reduces total immunoglobulin E, making immunotherapy safer.

Allergic Rhinitis: Overview

Many randomized, double-blinded controlled trials for allergic rhinitis in reaction to airborne pollens, animal allergens, and house dust mite aeroallergens demonstrate efficacy of allergen immunotherapy based on subjective symptoms scores and medication diaries. Favorable immunological changes include decreased basophil histamine release, reduced skin test allergen reactivity and increased allergen-specific IgG blocking antibody. A significant reduction in CD4+ IL-4+ cells is seen in the highest dose with immunosuppressive properties being linked to induction of CD4+CD25+ regulatory T-cells producing 11-10, TGF-p, or both.

Table  Proposed Sequence of Events for Successful Immunotherapy

Pollen

Nasal challenge studies enable investigators to measure the allergic response in the upper airway following allergen immunotherapy. Such research demonstrates that there is a dose response to ragweed allergen immunotherapy, i.e., an optimal dose above which little or no additional improvement occurs. The first of these studies involved 12 ragweed-sensitive subjects who received immunotherapy, Antigen E (AgE, now known as Amb a 1, the principal ragweed pollen allergen) injections for 3-5 yr, and results were compared to those in 27 untreated control subjects. Nasal provocation studies of treated subjects revealed that AgE immunotherapy decreased the clinical response to ragweed and decreased the allergic inflammatory mediator responses (histamine, prostaglandin D2 [PGD2], TAME-esterase, and kinins) to an intranasal ragweed challenge. In a later study, 26 previously nonimmunized, ragweed-sensitive subjects were randomized to three different dosage regimens (low to high doses; 0.6-25 (µg AgE/injection) and their responses to ragweed nasal challenges compared. The low-dose immunotherapy regimen provided no protective effect, whereas the moderate dose and high dose caused significantly reduced mediator release from the nasal mucosa following ragweed nasal challenge. Symptom scores, recorded by the moderate- and high-dose-treated subjects over three ragweed seasons, also improved significantly and correlated with the decreased release of inflammatory mediators. There was no significant difference in the degree of clinical improvement between the moderate- and high-dose groups.

Table Illustrative Dose Schedule for Short Ragweed Allergen Immunotherapy

1:10 Weightby volume (w/v) means that 1 g of pure pollen is diluted in 10 mL of diluent. l:10w/ v of standardized ragweed vaccine contains 400 ug Amb a 1 (Antigen E)/mL. Maintenance dose of immunotherapy is administered on a weekly to monthly schedule and can be altered on an individual basis. The above schedule represents a weekly injection schedule (week 1-20). More rapid build-up can be accomplished by giving the injections twice weekly or by utilizing a “rush” immunotherapy protocol that achieves maintenance doses in days rather than weeks.

Nasal challenges also confirm that such therapy attenuates both the immediate- and late-phase allergic responses by decreasing mucosal membrane cellular influx and mediator production. Ragweed immunotherapy for 3-5 yr is required to achieve clinical remission. Both mixed- and single-grass pollen immunotherapy studies for hay fever result in significantly decreased symptom-medication scores during the grass pollen season and responses to grass skin testing and nasal challenge testing. Increases in grass-specific IgG-blocking antibody occurs in subjects successfully treated with mixed-grass immunotherapy. The size of both the immediate- and late-phase skin tests to timothy grass vaccine were diminished in a timothy allergen immunotherapy study.

Mountain cedar tree pollen immunotherapy decreases symptom-medication scores during the cedar tree pollen season, reduces the late-phase skin test reaction to mountain cedar pollen diagnostic vaccine, and increases the specific IgG and decreases the seasonal rise in specific immunoglobulin E during the mountain cedar pollination season. Similar clinical and immunological results were obtained in birch pollen allergen immunotherapy trials. In addition, birch pollen nasal provocation studies show inhibition of allergic symptoms and reduced chemotactic activities for eosinophils and neutrophils in nasal secretions after allergen immunotherapy.

Mites, Molds, and Animal Danders

House dust mite allergen immunotherapy results in significantly decreased nasal symptom scores, responses to nasal allergen challenge, and size of the skin test reaction. The same changes in specific IgG and immunoglobulin E as observed with pollen studies were found. Alternaria spp mold immunotherapy produced similar decreases in nasal symptom-medication scores, allergen provocative challenges in the skin and nose, and increased serum IgG. Cat allergen immunotherapy results in reduced nasal symptom scores of subjects exposed to a cat in a study room.

Allergic Asthma: Overview

More than 50 controlled immunotherapy trials have been performed with a variety of allergens for seasonal, perennial and animal-induced asthma. Vaccines of rye grass, mixed grasses, ragweed, birch, mountain cedar, Alternaria spp, Cladosporium spp, house dust mites, cat, dog, and cockroach have been used in these trials. Collective analysis of these studies provides important insight, but comparisons among studies are difficult because of varied study designs. Of these studies, 42 demonstrated significant clinical improvement in treated subjects; 23 of these showed a significant increase in the bronchoprovocation threshold to the allergen used for immunotherapy. Of the trials in which immunological parameters were monitored, 16 demonstrated an increase in allergen-specific IgG-blocking antibody, and one showed a decline in specific immunoglobulin E. Nine reported decreased skin test reactivity to the allergen used for immunotherapy, and two demonstrated reduced in vitro basophil histamine release following allergen challenge. An overall analysis of controlled studies in the treatment of asthma with allergen immunotherapy indicates clinical efficacy in allergic asthmatics.

A meta-analysis of most published, controlled trials of allergen immunotherapy in asthma reviewed in the Cochrane Database (2003) indicates that allergen immunotherapy is effective in the treatment of allergic asthma, provided that the clinically relevant and unavoidable allergen can be identified. Between 1954 and 1997, 54 published randomized controlled trials satisfied the strict inclusion criteria of the Cochrane Database. There were 25 studies reporting immunotherapy for dust mite allergy, 13 studies of pollen allergy, 8 studies of animal dander allergy, 2 studies of allergy to the mold Cladosporium spp, and 6 studies that attempted simultaneous immunotherapy for multiple aeroallergens. A review of 75 additional studies by the Cochrane Database (1996-2001) indicates benefits from immunotherapy in asthma treatment. It was found that allergen-specific immunotherapy significantly reduced asthma symptoms and medication requirements, but there was no consistent effect upon lung function. Allergen immunotherapy reduced allergen-specific bronchial hyperreactivity to a greater extent than nonspecific bronchial hyperreactivity. It is not possible to compare the size of improvement with immunotherapy to that obtained with other therapy for asthma. Immunotherapy must be considered for use when asthma is extrinsic or allergic and unavoidable clinically relevant allergens are identifiable. The arguments favoring immunotherapy are especially strong in the case of younger patients requiring year-round medical management. If allergen immunotherapy is utilized, it should be administered in sufficiently high doses of vaccine to maximize the benefits. With these optimal doses, there is the expectation of a reduction in medication requirements and symptom scores in the majority of treated patients.

The National Heart, Lung, and Blood Institute (NHLBI) in 2001 sponsored an expert panel to establish guidelines for the diagnosis and management of asthma. This national asthma education and prevention program states that 75-85% of asthmatic patients are allergic, and immunotherapy should be considered in such patients when avoidance of allergens and treatment with appropriate medications does not control the disease. Immunotherapy decreases asthma medications, offsetting its own cost, and it may further reduce costs by decreasing need for concurrent treatment of allergic rhinitis.

Pollen

Allergic asthmatic subjects often experience increased bronchial hyperactivity during a specific pollen season. The effect of birch pollen allergen immunotherapy on bronchial reactivity, as measured by methacholine provocation, was investigated in subjects with birch pollen asthma induced during the birch pollen season. Untreated subjects had increased bronchial hyperreactivity to methacholine, whereas those receiving birch pollen immunotherapy did not. In addition, eosinophil cationic protein, an inflammatory mediator derived from eosinophils in the bronchoalveolar lav age fluid, was decreased in subjects receiving birch pollen immunotherapy. Other studies using mixed grasses, cedar, birch, mugwort, and ragweed pollen vaccine immunotherapy demonstrate reduced bronchial responses to methacholine or histamine.

The benefits of immunotherapy are specific for the allergen(s) used in treatment. Some studies have shown that single-pollen allergen immunotherapy, such as derived from one grass species, may provide incomplete relief of asthmatic symptoms because of multiple grass sensitivity or because other sensitivities exist, for example, to molds. Similarly, a highly purified standardized ragweed allergen vaccine containing only a single protein allergen, such as ragweed AgE or Amb a 1, may provide incomplete relief of symptoms in ragweed-sensitive asthmatic subjects because they are sensitized to several ragweed proteins besides the allergenic protein in the vaccine.

The immunoglobulin E immune response of asthmatic subjects is different in the polysensitized vs the mono sensitized subject. Patients sensitized to a single allergen have significantly lower total serum immunoglobulin E levels than those allergic to multiple allergens. The lymphocytes from the polysensitized subject, when challenged with allergen, release significantly more IL-4 (favors immunoglobulin E production) and CD23 (low-affinity immunoglobulin E receptor) in vitro than those from the mono sensitized subject, although the lymphocyte IFN-y in vitro production is the same in both groups.

A double-blind placebo-controlled study during the pollen season compared the efficacy of immunotherapy in monosensitized (orchard grass pollen) and polysensitized (multiple pollen, including orchard grass) asthmatic subjects. Subjects allergic to grass pollen were treated with an optimal maintenance dose of a standardized orchard grass pollen vaccine, whereas those allergic to multiple pollen species, including grass, received the same biologically equivalent dose of all standardized allergens to which they were sensitized. The results indicated that monosensitized subjects with orchard grass pollen allergy, but not polysensitized subjects, were significantly protected during the respective pollen season during this study. Higher doses of standardized vaccines over a prolonged treatment schedule are probably required to demonstrate efficacy in polysensitized allergic patients.

A 5-yr study of the role of immunotherapy in ragweed-induced asthma was published in 1993. Clinical parameters (symptom diary scores, medication usage, peak expiratory flow rate [peak expiratory flow rate] measurements and physician evaluations) and other end points (skin test sensitivity, serological parameters, and bronchial sensitivity to ragweed and methacholine) were monitored. A standardized, maintenance dose of ragweed vaccine containing Amb a 1, 10 µg/injection, was used to immunize ragweed-sensitive subjects. Both clinical and objective parameters improved, again demonstrating that the use of an appropriate therapeutic dose is necessary to achieve a good clinical response.

Creticos et al. in 1996 examined the efficacy of allergen immunotherapy for asthma exacerbated by seasonal ragweed exposure; 64 patients completed 1 yr of the study treatment, and 53 completed 2 yr. These patients were not exclusively ragweed sensitive. The immunotherapy group had reduced hay fever symptoms, skin test sensitivity to ragweed, sensitivity to bronchial challenges, and increased IgG antibodies to ragweed as compared with the placebo group. The seasonal increase in immunoglobulin E antibody to ragweed allergen was abolished in the immunotherapy group after 2 yr. Patients received doses of 4 µg/injection of Amb a 1 the first year and 10 µg/injection the second year. Although positive effects were observed in the immunotherapy asthma group, the clinical effects were limited. Both groups (immunotherapy and placebo) had some improvement in asthma symptoms during the study.

Role of Allergen Immunotherapy in Asthma Management

•   A consideration in asthmatics who are allergic: 80% of children over age 2 yr; 50% of adults.

•   A possible therapy in asthmatic, with concomitant significant allergic rhinitis — uncontrolled with environmental allergen elimination, plus rhinitis medication.

•   An adjuvant therapy in moderate-severe asthmatics who are not well managed with environmental allergen elimination plus asthma medication.

Adkinson et al. in 1997 performed a controlled trial of immunotherapy for asthma in allergic children. A placebo-controlled trial of multiple-allergen immunotherapy in 121 allergic children with moderate to severe perennial asthma was conducted over 2 yr. The median medication score decline was not significantly different between the immunotherapy group and the placebo group. The number of days patients received oral corticosteroids were similar in the two groups. There was no difference between the groups in the use of medical care, symptoms, or peak flow rates. Partial or complete remission of asthma occurred in 31 % of the immunotherapy group and 28% of the placebo group. The median PC20 for methacholine increased significantly in both groups, but there was no difference between the two study groups. Optimal doses of immunotherapy, ranging from 4.3 to 26 µg/injection, resulted in a mean 8.8-fold increase in the levels of allergen-specific IgG to Dermatophagoides pteronyssinus and D.farinae mites, short ragweed, oak, and grass. A 61% mean reduction in wheal diameters by prick skin testing to each respective allergen was observed. The group that benefited from immunotherapy was made up of children with milder disease (no inhaled corticosteroids) and younger children (<8.5 yr) with a shorter duration of disease. The data indicate that there is no discernible benefit from immunotherapy in allergic children with perennial asthma who already are receiving appropriate and optimal medical treatment from asthma experts.

Mites

Several studies of immunotherapy with vaccines of standardized aqueous D. pteronyssinus and/or D. farinae house dust mites demonstrate significant benefit. A study by Bousquet et al. revealed that among subjects allergic only to D. farinae, children show significantly greater improvement than adults. As expected, patients with severe, chronic asthma (FEVj > 70% of predicted), other perennial allergen sensitivities, aspirin intolerance, or chronic sinusitis achieve the least benefit from immunotherapy.

A later study by Bousquet et al. analyzed immunotherapy to D.pteronyssinus in 74 mite-allergic asthmatics. It demonstrated a significant dose-dependent increased tolerance to the standardized D. pteronyssinus allergen, Der p 1, on bronchial allergen challenge in each of the immunized groups vs no change in the control group. A significant reduction in hista-mine bronchoprovocation hyperresponsiveness also was observed, with the greatest reduction in the highest-dose group. The rate of systemic reactions was lowest in the low-dose and highest in the high-dose group, and since the 7 and 21 µg/injection schedules were equally effective, the 7 µg/injection dose was recommended as the appropriate target dose.

Danders

Several controlled studies found that cat and dog immunotherapy effectively increases the threshold dose of cat or dog dander vaccine, respectively, needed to induce a positive bronchial challenge in subjects with cat- or dog-specific allergic asthma. Such therapy also results in a reduction of symptoms after dander exposure in a challenge room. Many subjects are given cat or dog immunotherapy, at their own request, in an effort to better tolerate the presence of a pet in their home. However, confirmation of clinical efficacy, under such circumstances, is needed, and elimination of the animal from the environment in which the subject lives is the preferable mode of therapy. There is increasing evidence that the allergens of fur-bearing pets are ubiquitous in many homes and other indoor locations, even where no animals reside. It is being passively introduced into these locations because of the prevalence of such animals in US homes. Including cat and/or dog allergens in the vaccine of a patient with positive skin tests to cat and/or dog may become more commonplace.

Molds

Molds that trigger asthma are numerous, diverse, and contain multiple allergens, and mold vaccines available for use in the United States are not standardized. Controlled immunotherapy trials with standardized vaccines of Alternaria spp and Cladosporium spp demonstrate efficacy in the treatment of asthma. One such trial of 1 yr of treatment with Alternaria spp resulted in ablation or a reduced late-phase response upon Alternaria spp allergen challenge in 8 of 10 subjects. Increased concentrations of allergen and methacholine also were required to induce bronchial constriction. Cladosporium herbarium vaccine immunotherapy produced significant decreases in symptom-medication scores and response to bronchial challenge tests.

Local Reactions

Patients receiving allergen immunotherapy often experience reactions at the site of the injection (erythema and edema) that cause some local discomfort. No adjustment in vaccine dose is necessary for reactions less than 4 mm in size. Large local reactions, 4 cm or greater in diameter, occur less frequently and may cause more discomfort and persist for 24 h or longer. There is a concern that subsequent increases in the dose of the vaccine following a large local reaction may result in a systemic reaction; however, there is little evidence that such local reactions, whatever their size, place the subject at increased risk for a systemic reaction. This local discomfort can be controlled with cold compresses and oral antihistamines. When such reactions occur, the subsequent allergen immunotherapy dose usually is reduced to the previously tolerated dose and subsequently increased. If large local reactions persist, either the dose has to be divided into two doses given at separate sites or the same dose maintained, if tolerated, or the dose decreased. Large local reactions do not predict the onset of a subsequent systemic reaction, and most systemic reactions occur in the absence of previous large local reactions.

Risk of Systemic Reactions to Allergen Immunotherapy

•  Risk rate: 1 per 2000 injections.

•  Most reactions begin within 30 min of injection — thus, a minimum of 30 min waiting time is advised.

•  More systemic reactions occur:

In highly allergic patients.

With use of pollen-allergen vaccine, especially during the pollen seasons.

During initial dose “buildup” phase, especially with accelerated programs.

•  The risk of more serious reactions is increased:

In allergic asthmatics.

With patients taking concomitant p-blocking drugs

Systemic Reactions

Systemic reactions occur rarely; they may range from mild, manifested as generalized pruritus, urticaria, or symptoms of allergic rhinitis and conjunctivitis, to life threatening, with upper and lower airway obstruction and/or anaphylactic shock. Fatalities are rare but do occur. A retrospective survey by questionnaire of allergy specialists in the United States for the period 1945-1983 reported 46 fatalities either from skin testing or immunotherapy. The data from 30 questionnaires allowed further evaluation of the fatalities; 6 were caused by skin testing and 24 by immunotherapy. A later extension of this study included reports of an additional 17 deaths between 1985 and 1989. Further reporting has disclosed another 41 fatalities related to immunotherapy from a survey from 1990-2001.

The incidence of systemic reactions from immunotherapy over a 10-yr period at the Mayo Clinic was 0.137%; most were mild and responded to immediate medical intervention. There were no fatalities. The estimated fatality rate from allergen immunotherapy in the United States was approximately one per 2-2.8 million injections. Some factors cited that increased the likelihood of a systemic reaction are an incorrect injection technique or erroneous dose. This type of mishap was not the cause in all systemic reactions. Other observations were (1) mite-sensitive individuals had more immunotherapy-related asthma reactions than those who were pollen sensitive; (2) fewer reactions occurred with maintenance doses than during the build-up phase; (3) excluding the severe or unstable asthmatic from receiving the immunotherapy injections significantly reduced the rate of systemic reactions.