Immunotherapy was first used successfully in 1911 by Leonard Noon, who noticed that in many people the onset of allergic symptoms coincided with the pollination of grass in England. He found that intradermal injections of an extract of grass pollen relieved the signs and symptoms that patients experienced during the grass pollen season.

Since that time, the use of immunotherapy has greatly increased. According to the American Academy of Allergy and Immunology, approximately 33 million injections are given per year in the United States. Immunotherapy appears to be effective for the treatment of allergic rhinoconjunctivitis and for insect sting allergies. (The use of immunotherapy for insect sting allergies is not discussed in this article.) There is healthy debate on the effectiveness of immunotherapy in the treatment of asthma, with opinions varying from “effective” to “completely ineffective.” However, some authorities argue that the risks of immunotherapy exceed the benefits in patients with unstable asthma.

At present, no evidence points to the effectiveness of immunotherapy for urticaria, atopic dermatitis and food allergy. Although preliminary data suggest that immunotherapy may be effective for the treatment of food allergy, use of immunotherapy for this purpose is fraught with danger. Until further data are available, immunotherapy for food allergy should probably not be undertaken outside of research settings.

Indications

Table 1 summarizes the indications for immunotherapy. Immunotherapy has traditionally been attempted in patients with a history of IgE-mediated disease that correlates with positive results on skin testing or radioallergosorbent testing (RAST). Before the decision is made to administer immunotherapy, environmental control measures, including avoidance of the offending agents, should have been tried and should have been shown not to result in improvement of symptoms. In addition, either an incomplete response to medications has been observed or the patient has made the decision not to take medications. A trial of immunotherapy is warranted if these criteria are met and contraindications do not exist.

The cost of the buildup phase during the first year of immunotherapy varies, depending on the number of injections required and the extracts used. Maintenance therapy may range from $200 to $1,000 per year, depending on the number of injections given and physician fees.

Immunotherapy in Allergic Rhinitis

Biochemical changes in the mucosa and the nasal secretions occur following immmunotherapy for allergic rhinitis.¹ When compared with placebo, immunotherapy has been shown to be associated with decreased concentrations of histamine, tosyl-L-arginine methyl esterase (or TAME, the esterase that can activate the bradykinin system) and prostaglandin G₂. This effect suggests that, as a result of immunotherapy, there is a reduction in the release of mediators by mast cells, an important component during the early phases of the immune reaction in allergic rhinitis.¹

Immunotherapy can also inhibit the influx of inflammatory cells, such as eosinophils. Eosinophils are thought to be a key component in the late phase of allergic rhinitis. The late phase seems to be responsible for the priming effect, which causes worsening of symptoms from day to day in the face of similar antigen exposure. Thus, immunotherapy not only decreases mast cell mediator release but also the inflammatory response associated with allergic rhinitis.²

Changes in the immune system also occur with immunotherapy. Early in therapy, the IgE level increases, prior to the increase of the IgG level. It is at this time that patients may be at the greatest risk of anaphylaxis and other adverse effects of immunotherapy.³ Later, IgG levels specific to the allergen used for treatment increase as total IgE and specific IgE levels decrease.

Studies of immunotherapy for allergy to ragweed in the eastern part of the United States and to grasses in the western United States have demonstrated a reduction in symptoms and medication use when patients receive immunotherapy as compared with placebo injections.^4,5 Improvement in symptoms is limited only to the pollen season for the particular extract that is being administered—thus, the reaction is specific. This effect persists during the course of immunotherapy and, probably, for years after completion of a full course of immunotherapy.⁶

Immunotherapy in Asthma

Asthma is a multifactorial disease. Exercise, industrial and occupational agents, weather changes, viral infections, medications (e.g., aspirin), emotions, tobacco smoke and particulate matter may all trigger symptoms of asthma. Allergens are an important aspect to consider in the management of asthma, but allergens are not the only triggers that need to be controlled.

In patients with asthma, there is a trend toward a lower correlation between asthma symptoms and allergy with increasing age. It is estimated that 90 percent of children with asthma have allergic disease; sensitivities include house-dust mites (52 percent of patients), animal dander (29 percent), pollens (20 percent), molds (14 percent) and cockroaches.⁷ Therefore, when possible, skin testing or RAST testing is essential to define the allergic component of asthma, and these data should be used to direct appropriate environmental changes. Multiple studies have been performed stressing the importance of avoidance measures and techniques to accomplish avoidance in persons with asthma.^7–9 However, data to support the use of immunotherapy in asthma are less concrete.

A recent study investigated the effectiveness of immunotherapy in patients with asthma.¹⁰ Screening for ragweed allergy was conducted in 1,000 patients with asthma, and 77 patients (7.7 percent) were found to have ragweed sensitivities that met criteria for inclusion in the study. Overall symptom improvement and decreased use of medications were noted in the group receiving immunotherapy, but only in the first year of therapy. Peak flow values improved, as did the response to an inhalation challenge with ragweed. As would be expected, IgE levels decreased and an increase was noted in the IgG level that is specific for ragweed. This finding suggests that there is benefit from immunotherapy in patients with asthma. However, the study revealed no cost savings with the use of immunotherapy compared with drug therapy.

There have been two recent attempts to perform a meta-analysis on immunotherapy studies.^11,12 Abramson and colleagues¹¹ conducted a meta-analysis on studies that were randomized and properly controlled. The studies were performed between 1966 and 1990. Some of them were done without high-dose therapy (antigen levels that have been demonstrated in the literature to be effective in inducing desensitization) or standardized extracts (extracts with a defined level of a specific antigen that can be reproduced from lot to lot). Of the studies reviewed, nine focused on house-dust mites, five on pollens, five on animal dander and one on mold allergy. The meta-analysis demonstrated that immunotherapy is associated with a reduction in symptoms, a decreased need for asthma medications and a reduction in bronchial hyperreactivity. The authors concluded from this meta-analysis that immunotherapy is effective for the treatment of asthma, but it should be used with caution because it may also exacerbate asthma symptoms in some patients.

The second meta-analysis, performed by Sigman and Mazer,¹² focused on the use of immunotherapy in children with asthma. Twelve studies were reviewed. The authors found a lack of uniformity across the studies, which limited the ability to do a true meta-analysis. The analysis indicated that four of five studies showed some effectiveness of immunotherapy in mite-allergic persons. The data available for animal dander and fungi were limited, and no conclusion could be drawn. The benefit of pollen immunotherapy was also questionable. Because of the safety factors associated with the use of immunotherapy, Sigman and Mazer were unable to conclude that immunotherapy should be used in asthma. They stated that well-performed, well-controlled clinical studies are needed to define whether immunotherapy is an effective treatment in children with asthma.

Adverse Effects

Adverse effects from immunotherapy are common. Fortunately, the vast majority of these effects are minor and mainly consist of local swelling at the site of injection. One study¹³ revealed that 1 to 50 percent of patients receiving immunotherapy injections experience some type of adverse effect. The incidence of adverse effects per 1,000 injections is between one and 17. Our experience suggests that approximately 15 percent of patients experience adverse effects. The risk increases under each of the following circumstances: “rush” therapy (desensitization accomplished over one day to a few days), the use of high doses and immunotherapy introduced without premedication.

Patients at risk of adverse effects include those with a history of frequently large local reactions, asthma, a recent use of steroids, and a recent hospitalization or emergency department visit for asthma therapy. The risk is also increased in patients with signs or symptoms of asthma before their injection¹³ (Table 2).

A review¹⁴ of data on immunotherapy-related fatalities in the United States shows that there were 24 deaths from 1959 to 1984 and 17 deaths from 1985 to 1989. Asthma had been diagnosed in 13 of the cases, and most of these patients had unstable asthma during the time they were receiving immunotherapy.

A more recent review¹⁵ of adverse effects of immunotherapy revealed that patients at highest risk of adverse effects were those with strongly positive skin tests, those receiving immunotherapy during the season in which they were allergic, those with a history of prior anaphylaxis and those with a diagnosis of asthma. Adverse effects were also increased when vials were changed, independent of whether the change in vials occurred during the buildup or the maintenance phase of the program. A risk-benefit analysis should be done in such patients to determine whether immunotherapy should be started or continued.

To decrease the risks associated with immunotherapy, it should be administered cautiously in all patients with asthma. A peak flow test should be done prior to injection and should be above 70 percent of the predicted value (or above 70 percent of the patient's personal best) before an injection is administered. For patients who are at high risk of adverse effects, a peak flow value should be determined before the patient leaves the office to ensure that there is no decrement after the injection. Some authors have suggested that children under the age of five should not receive immunotherapy because of the increased risk associated with bronchospasm in this age group.¹⁶

Guidelines for the Use of Immunotherapy

Because of the risk of anaphylaxis, recent guidelines have been published to properly identify patients who should (or should not) receive immunotherapy.^17,18 The Canadian Society of Allergy and Clinical Immunology published guidelines in 1995.¹⁷ The consensus is that immunotherapy should be administered only with a specific allergen when patients have documented IgE disease and have not improved following avoidance techniques. Before immunotherapy is initiated, a failure of control of symptoms with medications should be documented. Patients who have autoimmune disease or uncontrolled asthma or who are are under the age of five should not receive immunotherapy because the risks of such therapy exceed the benefits. If immunotherapy failed to alleviate the symptoms in the past, a second trial should not be attempted. If the patient's symptoms do not respond within the first two years of immunotherapy, the attempt should be discontinued. Lastly, the guidelines suggest that high-dose therapy should only be used for a maximum of five years.

The American Academy of Allergy and Immunology published immunotherapy guidelines in 1994.¹⁸ This consensus suggests that immunotherapy should not be self-administered by the patient. Rather, it should be administered in a physician's office, with a physician in the immediate vicinity. The physician should be knowledgeable in both the treatment of anaphylaxis and the administration of immunotherapy. Patients with asthma should be observed for 30 minutes after an immunotherapy injection. The suggested emergency equipment that should be available in the office is listed in Table 3. Of note, defibrillation equipment is not considered essential.

Even though alternate routes of administration are being investigated, the standard of care is still the use of subcutaneous immunotherapy. High-potency and, in most cases, standardized extract should be used. Appropriate dose reductions should be made if local reactions are large, systemic adverse effects are noted, delays in therapy occur or the vials are changed. One or two nurses who are knowledgeable in immunotherapy administration should be responsible for the program, and informed consent should be obtained before starting immunotherapy. As with any other injection, universal precautions should be maintained.

Contraindications

Relative and absolute contraindications to immunotherapy are listed in Table 4. Pregnancy is not an absolute contraindication. Once a patient is receiving maintenance therapy, the risk of anaphylaxis is minimal and, thus, immunotherapy can be continued during pregnancy as long as there is no prior history of adverse effects. Initiation of immunotherapy during pregnancy is too risky, however, and should not be done.¹⁷

Although no evidence suggests an increased incidence of autoimmune diseases in patients who are receiving immunotherapy, the concern is that an increased production of IgG stimulated by immunotherapy may be a risk factor for the development of immune complex–mediated disease. Thus, most authorities recommend not administering immunotherapy in patients with a history of autoimmune disease.¹⁷

Patients who have unstable coronary artery disease or who are receiving beta-adrenergic blockers are at increased risk of death from anaphylaxis and are also at risk from the intervention (epinephrine) needed to treat anaphylaxis. Such patients should not receive immunotherapy.¹⁴

Children under the age of five also should not receive immunotherapy. Small-caliber airways result in a smaller respiratory reserve; therefore, children younger than age five are at increased risk of respiratory problems associated with immunotherapy. Similarly, patients with unstable asthma who have a forced expiratory volume in one second (FEV₁) or a peak flow value below 70 percent of predicted value should not receive immunotherapy because of their decreased respiratory reserve secondary to the underlying disease.¹⁶

Patients who repeatedly exhibit large local reactions should be given a reduced dose to decrease the risk of systemic reactions. If a patient has had systemic reactions in the past, immunotherapy is potentially dangerous and should be avoided.

Preparation of Extracts

Immunotherapy doses should be mixed only by those well trained and experienced in the preparation and dilution of immunotherapy. Extracts that are used to formulate immunotherapy can be obtained from multiple pharmaceutical companies. In most cases, patients present to the office with the dilutions already prepared. The physician prescribing the immunotherapy should instruct the physician who is administering immunotherapy on the storage of the preparation, precautions, dose adjustments and emergency procedures to follow if adverse effects occur. An alternative to mixing the extract is to directly order prediluted extract from a pharmaceutical company. In this case, the physician should prescribe the dosing schedule, dilutions and concentrations of the extract. Pharmaceutical companies should not prepare extract from RAST data, because clinical correlation is necessary to determine if a positive test is of significance. For example, a patient who has a positive test to ragweed but has never had symptoms during the ragweed season should not be desensitized to ragweed.

To decrease liability, deviation from the dosing schedule is not recommended. If the immunotherapy schedule needs to be adjusted or temporarily changed, an allergist or other physician who prepared the extract should be consulted. Immunotherapy schedules vary significantly, from very aggressive desensitization protocols, referred to as “rush protocols,” which can achieve maintenance levels in days, to conservative protocols in which maintenance may take months to achieve. The dosing schedule varies, depending on the extract concentration, the number of serial dilutions prepared, the expected risk for adverse effects and the patient's health.

To decrease the risks associated with immunotherapy, a quality assurance program should be in place. All vials should be appropriately labeled, and instructions should be easy to follow and read. Patients who have asthma should bring a peak flow meter with them to each appointment. As mentioned previously, their peak flow value should be above 70 percent of their expected value. Because of the small risk of a delayed reaction, patients may want to have self-injectable epinephrine, such as an Epipen, available at home. This is especially true for people who are at high risk of adverse reactions. Extending the waiting period from the usual 20 minutes to 30 minutes for patients most likely to experience adverse events may also decrease the risk of complications from a delayed reaction at home. Patients who are symptomatic, especially with signs and symptoms of asthma, should not receive their allergy injection that day.

A dose of subcutaneous epinephrine should be readily available in each room where immunotherapy is given so that the response to anaphylaxis can be rapid, to avert the progression of side effects associated with the use of immunotherapy.

Duration of Immunotherapy

Studies have demonstrated both short- and long-term benefits of immunotherapy. These benefits persist even after discontinuation of the immunotherapy. One study demonstrated that the IgE level, the signs and symptoms and the response to a histamine challenge showed continued improvement three to five years after discontinuation of immunotherapy.⁶ In general, immunotherapy is administered for three to five years. A trial of discontinuing immunotherapy should be attempted after three to five years of therapy.¹⁷

Alternative Forms of Immunotherapy

Recently, three alternative routes of immunotherapy have been attempted. These include sublingual, oral and intranasal immunotherapy.^19–21 In the United States, all three alternate routes of immunotherapy are considered experimental and are limited to use in research projects.