Allergy immunotherapy: Indications, efficacy, and safety

ABSTRACT:Although many effective pharmacological therapies are available for patients with allergies, only allergen-specific immunotherapy has been shown to have significant and longlasting therapeutic and immunomodulatory effects in the management of allergic rhinitis, allergic asthma, and venom hypersensitivity. Standard allergen immunotherapy consists of subcutaneous injections of relevant allergens. It requires a buildup phase during which the dose of the vaccine is increased until a therapeutic (maintenance) level is achieved. This maintenance dose is usually continued for 3 to 5 years, and most patients continue to do well after injections are discontinued. Most patients tolerate immunotherapy well, but local reactions are not uncommon. Immunotherapy should be administered only in a physician's office, because some patients may experience systemic anaphylactic reactions requiring immediate therapy. Even with newer therapies on the horizon, allergen immunotherapy will continue to have an important role in the treatment of allergic diseases. (J Respir Dis. 2008;29(3):136-141)

Allergic diseases have increased in prevalence over the past 20 years, affecting as many as 40 to 50 million persons in the United States. Since it was first described by Noon,¹ allergen immunotherapy has been used for nearly 100 years.

Allergen immunotherapy alters the course of allergic diseases through a series of injections of a mixture of extracts composed of clinically relevant allergens. The term "allergen extract" had been replaced by "allergen vaccine" by the World Health Organization until recently when the new term "allergen immunotherapy extract" was coined to define the mixture of extracts or the extract used for allergen immunotherapy.^2,3 Allergen extract refers to the source material not yet integrated into the vaccine. Other terms used for allergen immunotherapy include hyposensitization, desensitization, allergy shots, and allergy injections.

In this article, I will review the indications and contraindications of allergen immunotherapy and how it is administered. I also will discuss its efficacy and safety.

Mechanisms

The exact mechanisms of how immunotherapy works are not fully understood, but they involve shifting a patient's immune response to an allergen from a predominantly "allergic" T-lymphocyte (T_H2) response to a "nonallergic" T-lymphocyte (T_H1) response. Lymphocytes of a T_H2 phenotype typically produce interleukin (IL)-4 and IL-5, which are cytokines needed for IgE production and eosinophil survival, while T_H1 lymphocytes produce interferon gamma.

Allergen immunotherapy causes regulatory T cells to produce increased levels of IL-10.⁴ IL-10 causes a shift in allergen-specific IgE to allergen-specific IgG4, while the regulatory T cells down-regulate allergic immune responses in part through the release of IL-10 and transforming growth factor .

When allergen immunotherapy is administered, the seasonal increase in allergen-specific IgE is blunted while protective allergen-specific IgG4 production is increased. The effectiveness of allergen immunotherapy is not dependent on the reduction in specific IgE levels. Periodic skin testing and in vitro IgE antibody measurements are not useful in evaluating responses to immunotherapy.

Indications

Allergen immunotherapy is used in the treatment of allergic rhinitis, allergic asthma, and stinging insect venom hypersensitivity.^5-8 The diagnosis of these diseases is based on the history and physical examination findings, supported by testing to confirm IgE sensitization. Skin testing by prick or intradermal method is the preferred diagnostic technique, but in vitro tests, such as CAP RASTs, are an alternative, especially when skin testing cannot be performed. Patients who have specific IgE–positive test results but no corresponding clinical findings are not candidates for allergen immunotherapy.

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.^3,8 For a patient with venom allergy, the risk of anaphylaxis from an insect sting is greater than the risk of anaphylaxis from immunotherapy. In patients younger than 16 years who have only urticaria from Hymenoptera stings, immunotherapy is not generally recommended. However, in patients older than 16 years who have only systemic cutaneous reactions, immunotherapy is a recommended option. Venom immunotherapy is not indicated for patients who have had only local reactions-even large local reactions-at the stinging site.

Immunotherapy is also effective against inhalant allergens or aeroallergens, such as pollen, mold, animal dander, dust mite, and cockroach allergens. Patients with allergic rhinitis and asthma who are symptomatic despite allergen avoidance and pharmacotherapy are candidates for immunotherapy (Table 1).^3,5-7 Other candidates include those with allergic rhinitis or asthma who have undesirable adverse reactions to medications or those who wish to reduce or eliminate long-term pharmacotherapy.

In addition to reducing the symptoms that are associated with current allergens, immunotherapy may prevent the development of sensitization to new allergens or the progression of allergic rhinitis to asthma, especially in children.^3,9 Food allergy, chronic urticaria/angioedema, and atopic dermatitis are not acceptable indications for allergen immunotherapy. In patients with aeroallergen sensitivity who also have atopic dermatitis, there are limited data that immunotherapy may be beneficial.

Contraindications

The relative contraindications for immunotherapy include medical conditions that reduce the patient's ability to survive a serious systemic allergic reaction, such as coronary artery disease and severe uncontrolled asthma.³ The use of -adrenergic blocking agents (including those in eyedrops) may make the treatment of immunotherapy-related systemic reactions more difficult. Despite this, allergen immunotherapy is indicated for patients with life-threatening stinging insect hypersensitivity who are receiving -blockers, because the risk of stinging insect allergy is greater than the risk of immunotherapy-related systemic reactions.

Allergen immunotherapy should not be initiated in patients with asthma unless the asthma is relatively stable with pharmacotherapy. Currently, professional societies recommend that patients with asthma who have a forced expiratory volume in 1 second of less than 70% of the predicted value generally should not receive immunotherapy.

Patients who are mentally or physically unable to communicate clearly, such as very young children, are not good candidates for immunotherapy, since it may be difficult for them to report early symptoms of a systemic reaction. In addition, patients need to be cooperative and adherent.

Pregnancy is not a contraindication, but immunotherapy is not customarily initiated during pregnancy. If a patient becomes pregnant while already receiving immunotherapy, the dose is not increased during the pregnancy, but it is maintained at the current level in an attempt to avoid anaphylactic reactions.

Dosing

Standard allergen immunotherapy is administered as a subcutaneous injection. To prepare the vaccine, the allergist selects the appropriate allergen extracts 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.³

Standardized extracts should be used, when available, and may be mixed with nonstandardized extracts. Currently, the only standardized aeroallergen extracts available are dust mites, grass pollen, cat allergen, and short ragweed. For venom allergy, extracts are standardized based on venom content, except for those for fire ants, which use whole body extract. 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 maintenance concentrate should be prepared and labeled for each patient. The practice of mixing individual antigens in a syringe is not recommended. The effectiveness of immunotherapy depends on achievement of an optimal therapeutic dose of each allergen extract in the vaccine.

Allergen immunotherapy dosing consists of 2 treatment phases: the buildup phase and the maintenance phase.³ The prescribing physician must specify the starting dose, the target maintenance dose, and the immunotherapy buildup schedule. The effective therapeutic dose is referred to as the maintenance dose.

In general, the starting immunotherapy dose is 1000- to 10,000-fold less than the maintenance dose. For patients who are highly sensitive, the starting dose may be even lower. Dilute concentrations are more sensitive to degradation and lose potency more rapidly than the more concentrated preparations. Therefore, 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 protocol recommends dosing once or twice week with at least 2 days between injections (Table 2). Patients with greater sensitivity may require a slower buildup phase to prevent systemic reactions. The potential for increased systemic reactions during a patient's allergy season has led to more cautious dosing schedules during that time of year. 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 of 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 up to 4 weeks for inhalant allergens and up to 8 weeks for venom allergens but are individualized for each patient.

Clinical improvement can be demonstrated shortly after the patient reaches the maintenance dose. If no improvement is noted after 1 year of maintenance therapy, a reassessment should be done. Possible reasons for lack of effectiveness need to be evaluated, and if none are found, discontinuation of immunotherapy should be considered. Patients should be evaluated by the prescribing allergist/immunologist at least every 6 to 12 months while receiving immunotherapy.

The duration of maintenance therapy is usually 3 to 5 years. Treatment may lead to prolonged clinical remission and persistent changes in immunological reactivity. The severity of disease, benefits from sustained therapy, and the convenience of treatment are factors that are considered when deciding the length of therapy for each patient.

Many studies, especially those in Europe, have shown that high-dose sublingual allergen immunotherapy (SLIT) is effective in certain patients but is generally not as effective as subcutaneous immunotherapy.¹⁰ The greatest advantage of SLIT is safety. Local symptoms, such as mouth itching, are common, but systemic adverse effects are rare and no SLIT-related fatalities have been reported. Many questions about SLIT remain unanswered, including effective dose concentrations, schedule for buildup and maintenance therapy, and timing of dosing (seasonal or continuous).

In addition, SLIT requires much larger doses of allergen (up to 500 times more than subcutaneous immunotherapy), and at this time, no FDA-approved extracts are available. Finally, the appropriateness of SLIT for polysensitized patients has not yet been determined.

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 by taking H1 antagonists before injections. Local reactions can be managed with treatments such as cold compresses or topical corticosteroids. Large, local, delayed reactions (25 mm or more) do not appear to predict severe systemic reactions and generally do not require adjustment of dosing schedules.³ However, some patients who have more frequent large local reactions (more than 10% of injections) may be at increased risk for future systemic reactions, and dosing adjustments may be necessary.^3,11

The prevalence of severe systemic systemic reactions after allergen immunotherapy ranges from less than 1% in patients receiving conventional immunotherapy to more than 36% in patients receiving rush immunotherapy.^3,12 Risk factors for systemic reactions include errors in dosing, symptomatic asthma, a high degree of allergen hypersensitivity, concomitant use of -blocker medications, injections from a new vial, and injections given during periods when allergic symptoms are active (especially during the allergy season).³

A 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.¹³ These errors resulted in many adverse events, including local reactions, systemic reactions, and 1 fatality. Therefore, it is essential to make sure that patients are questioned about potential risk factors and that the correct vials are used to administer immunotherapy injections.

Premedication with antihistamines may reduce the frequency of systemic reactions in conventional immunotherapy. In cluster, or rush, immunotherapy, premedication with antihistamines and, when appropriate, prednisone should be given before injections.

The incidence of fatalities due to immunotherapy has not changed much over the past 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.¹⁴ Most fatal reactions occurred with maintenance doses. The patients at greatest risk were those with poorly controlled asthma. 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 and/or hypotension requiring epinephrine) is 2.5 times higher than the incidence of fatal reactions.¹⁵

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 occur alone or with skin manifestations in 42% of systemic reactions.

Epinephrine is the standard of care for systemic or anaphylactic reactions.¹⁶ Treatment of anaphylactic reactions includes placing a tourniquet above the injection sites and immediately injecting epinephrine 1:1000 (1 mg/mL) 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), given 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

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, particularly anaphylaxis. A full, clear, and detailed documentation of the patient's immunotherapy schedule must accompany the patient when he or she is receiving injections at another health care facility.

Because of the potential for anaphylaxis, immunotherapy should not be administered at home. Informed consent should be obtained before administering immunotherapy. 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 patient. The American Academy of Allergy, Asthma and Immunology's recommended nomenclature and color-coded system is shown in Table 3.³

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

Most severe reactions develop within 20 to 30 minutes after the immunotherapy injection, but reactions can occur later. Patients need to wait at the physician's office for at least 30 minutes after the injection. In some cases, they may need to wait longer depending on their history of reactions.

It is usual practice to reduce the dose of vaccine when the interval between injections is longer than prescribed (Table 4). This reduction in dose should be clearly stated on the patient's immunotherapy schedule. When new vials are started, the initial dose should be decreased and then built back up to maintenance because of the potential for extract degradation over time and because of the variability in potency of extracts from lot to lot in nonstandardized extracts.

When a systemic reaction occurs, the prescribing physician must decide whether immunotherapy should be continued. If the decision is to continue, the dose of the vaccine needs to be appropriately reduced to decrease the risk of a subsequent systemic reaction.

Efficacy and outcomes

Once maintenance dosing is achieved for venom immunotherapy, 80% to 98% of patients will be protected from the systemic symptoms of a sting.^3,8 Maintenance therapy is generally recommended for 3 to 5 years, with growing evidence that 5 years of treatment provides a 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 risk of a 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.⁵ These studies have shown significant improvements in symptoms, quality of life, medication use, and immunological parameters. Immunotherapy for allergic rhinitis has also been shown to be beneficial for at least 3 to 6 years after completion of a 3-year course of treatment. A general rule of thumb has been 70% of patients improve 70%.

The efficacy of immunotherapy for asthma has been assessed in many trials, but some studies have been difficult to interpret, with conflicting results either because of the use of poor-quality allergen extracts or suboptimal study design.^6,7 The risk:benefit ratio of immunotherapy for asthma must always be considered. A Cochrane review examined the role of allergen immunotherapy for asthma.⁶ This review of 75 trials with 3100 patients found that the administration of allergen-specific immunotherapy was associated with a significant reduction in asthma symptoms and medication use and improvement in bronchial hyperreactivity. It was concluded that immunotherapy was effective in patients with asthma and noted that one trial found that the size of the benefit was possibly comparable to that associated with inhaled corticosteroids.

Typically, studies evaluating the efficacy of inhalant allergen immunotherapy are conducted with single allergens. However, most patients in the United States have multiple allergic sensitizations and are treated with multiple extracts.

Summary

Allergen immunotherapy has been a valuable tool in treating allergic rhinitis, allergic asthma, and stinging-insect hypersensitivity for decades. Although newer pharmacological agents continue to become available, immunotherapy is still the only available treatment that alters the natural course of allergic diseases. There are some risks, but they can be minimized when immunotherapy is given to carefully selected patients in an appropriate environment. Recent guidelines have attempted 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 of the 40 to 50 million persons with allergies, many of whom could benefit from this therapy. Newer therapies, such as anti-IgE (omalizumab) therapy, may help improve the efficacy and safety profile of immunotherapy. In addition, newer forms of immunotherapy, such as T-cell peptides or immunostimulating sequences of DNA-containing CpG motifs combined with allergens, are under investigation, with early trials looking promising.

References:

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