Key Points
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Subcutaneous immunotherapy is an effective treatment for pediatric patients with allergic rhinitis and stinging insect hypersensitivity, and selected pediatric patients with allergic asthma.
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Sublingual immunotherapy is an approved and effective treatment for seasonal allergic rhinitis due to grass and ragweed pollen allergy.
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There is a small but real risk of systemic allergic reactions with immunotherapy, and the risk associated with subcutaneous immunotherapy appears to be greater than that for sublingual immunotherapy.
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Immunotherapy is associated with changes in humoral and cellular immune responses as well as effector cell responsiveness.
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Oral immunotherapy for food allergy is an active area of investigation.
In 1911, Noon found that by administering increasing doses of grass pollen extract, he could induce a marked decrease in conjunctival sensitivity to grass pollen. It was this observation that eventually led to the widespread use of immunotherapy for the treatment of allergic disease. Immunotherapy is the term used to describe a prolonged process of repeated administration of extracts of pollens or other allergen sources to patients with diseases with a demonstrable allergic etiology for the purpose of reducing symptoms. It has also been called desensitization or allergy injection therapy. It is recommended in most discussions of the treatment of allergic airway disease, along with allergen avoidance and symptomatic drug therapy.
Principles of Immunotherapy
In allergic rhinitis (AR), the effectiveness of immunotherapy has been demonstrated in many carefully conducted placebo-controlled trials. The results of a typical clinical trial are shown in Figure 23-1 . Three groups of patients matched on the basis of their allergic sensitivity to ragweed allergen were treated with injections of whole ragweed pollen extracts, purified Antigen E (Amb a 1) or placebo. Although everyone became symptomatic during the ragweed pollen season, it is obvious that those receiving placebo injections were more symptomatic than those receiving pollen extracts. These trials have been reviewed in detail elsewhere and are addressed here only to review the principles learned for the safe and effective use of immunotherapy.
The first principle is that clinical effectiveness is dose dependent; that is, a certain minimal dose of allergen extract must be administered to produce effective symptomatic control. These extracts are prepared by suspending source material (pollen, fungal cultures, dust mites or animal pelts) in buffers to extract the water-soluble components into the buffer, and they are now available commercially under license by the US Food and Drug Administration (FDA). Extracts are complex mixtures of dozens of proteins, of which only a few are major allergens. Clinical trials that compare treatment with purified allergens or with partially purified extracts containing high concentrations of allergens with treatment with currently available crude extracts have shown them to be equally effective. For instance, symptoms are reduced to a similar extent with immunotherapy with purified ragweed allergen Amb a 1 and with whole ragweed extract in the study illustrated in Figure 23-1 .
Another lesson from these studies is that therapeutic effectiveness of conventional immunotherapy increases with time. Significant improvement is generally not seen before 3 months or more of therapy. It is not clear why such a long time is needed, but in part it reflects the time required to increase the injected dose from the very small dose that can be tolerated initially to the 10,000-fold higher dose that produces immunologic and clinical effects. It is also obvious that immunologic effects must be taking place very early in this process to allow the patient to tolerate increasing doses without anaphylaxis. Clinical benefit increases for several years after the maximal doses of antigens are achieved. Although the reason for the delayed effect of immunotherapy is not clear, it is important to discuss with patients so that their expectations will be realistic. It is important to note, however, that single dose sublingual immunotherapy, which has recently been approved in the United States for grass and ragweed allergy, has a more rapid onset of action, likely because no build-up phase is required, and is efficacious when given only part of the year, prior to and during the relevant pollen season.
In clinical trials when symptom scores are compared with those in untreated patients, a placebo effect is consistently seen. This placebo effect is especially easy to see in the asthma trials, in which most placebo-treated patients improve and 25–30% improve significantly. For clinical investigators, this fact has made it absolutely essential to include a placebo group in any immunotherapy trial. For clinicians, it is important to recognize that there is a significant and powerful placebo effect associated with the repeated injections and frequent visits with sympathetic physicians and nurses. Only by administering concentrated antigen preparations to carefully selected patients are the benefits greater than those seen with sympathetic support.
For most patients, symptomatic improvement is partial and immunotherapy serves to decrease the severity of symptoms without totally eliminating them. In addition, a significant number of allergic patients, perhaps as many as 25%, do not benefit from IT regardless of the potency of the antigen or the length of therapy. The reasons why certain patients are ‘nonresponders’ are unclear, but the point is an important one to bear in mind when discussing immunotherapy with patients.
In clinical trials, systemic anaphylactic reactions are common. Although these are usually mild and not life threatening, they may require epinephrine therapy and may be fatal. Such reactions are not surprising because patients are selected who are clearly allergic on the basis of skin tests and/or specific immunoglobulin E (IgE) tests and history of severe symptoms on allergen exposure. In a recent large clinical survey, one fatality out of 23.3 million injection visits was identified, approximately one out of every 1 million injections resulted in a very severe, near-fatal reaction, and one out of every 1000 injections resulted in a systemic reaction.
Research in immunotherapy continues in several directions. Standardization of allergen extracts to make available products with consistent potency has dramatically increased the reliability of commercially available extracts. Studies have demonstrated the safety and efficacy of shortening the dose escalation phase with schedules for rush and ultrarush immunotherapy. Investigators have also been studying adjuvants to improve efficacy of immunotherapy as well as modified allergens to reduce the risk of serious reactions to immunotherapy. Other routes of administering allergen extracts are also being studied, as well as the use of immunotherapy for other allergic diseases such as eczema and food allergy. Finally, immunomodulatory therapies are currently in clinical trials; these include agents such as anti-IgE and anticytokine therapies.
Mechanisms of Action
Many observations about patients’ immunologic and cellular responses to immunotherapy have been made, but the precise mechanism of action of immunotherapy remains unknown. What is generally recognized is that skin test sensitivity decreases and allergen-specific IgG increases with immunotherapy. It is not until after several years of immunotherapy that allergen-specific IgE decreases. There has also been much speculation that immunotherapy acts on the T helper cell type 1 (Th1)/Th2 axis to shift the T cell phenotype away from the allergic Th2 phenotype. More recently, a growing body of evidence suggests that immunotherapy may promote regulatory T cells which may play a role in attenuating allergic symptoms.
Antibody Response and Immunotherapy
Studies have consistently demonstrated an increase in allergen-specific IgG and IgE within months of starting immunotherapy. One trial of ragweed immunotherapy in adults that examined allergen-specific antibody responses can be seen in Figure 23-2 . Subjects demonstrated significant dose-dependent increases in ragweed-specific IgG long before symptom relief was seen. Ragweed-specific IgE initially increased and did not decrease until years into therapy. Similar observations have been made by other investigators for both venom immunotherapy and inhalant allergen immunotherapy. It has been suggested that allergen-specific IgG acts as blocking antibody either by blocking antigen binding by IgE or by preventing aggregation of the high-affinity IgE receptor (FcεRI) at the cell surface. Although allergen-specific IgG levels do not correlate with clinical efficacy, the functional blocking activity of allergen-specific IgG does appear to correlate with clinical efficacy.
Effects on T Cells
Because a Th2 phenotype has been associated with allergic disease and a Th1 phenotype with protection against allergic disease, it has been hypothesized that immunotherapy exerts its effects through modulation of the T helper phenotype. This modulation may result in either a shift from the Th2 to Th1 phenotype or through induction of CD8 + suppressor activity. Indeed, evidence has been published in support of both of these hypotheses. Rocklin and colleagues demonstrated the generation of allergen-specific suppressor cells during immunotherapy and provided evidence that the suppressor cells decrease IgE synthesis. Other studies have examined the cytokine profile of peripheral blood Th2 cells and demonstrated decreases in interleukin (IL)-4 production and, in some cases, concomitant increases in interferon (IFN)-γ production, suggesting a modulation of the T helper phenotype from Th2 to Th1. The mechanism of these changes has recently advanced with the recognition of CD4 + CD25 + regulatory T cells that are capable of directing the Th1:Th2 balance and are activated by effective immunotherapy, as well as the more recent recognition of a role for regulatory B cells.
Effects on Inflammatory Cells
There also is evidence that immunotherapy affects mast cells, basophils and eosinophils. In the first few weeks of immunotherapy, it has been shown that the in vitro basophil response to allergen decreases sharply, just as it does during rapid desensitization regimens for patients with drug allergy. One study demonstrated a significant decrease in metachromatic cells (mast cells and basophils) in nasal scrapings after dust mite immunotherapy. Allergen-specific immunotherapy has also been demonstrated to decrease peripheral blood basophil histamine release. In addition, successful immunotherapy has been associated with a decrease in the numbers of eosinophils from nasal and bronchial specimens.
Specific disease indications
Allergic Rhinitis
Immunotherapy has been demonstrated to be quite effective in both seasonal and perennial AR. Many well-designed studies have examined the efficacy of immunotherapy for pollen-allergic patients with seasonal AR. These randomized, controlled trials have been the subject of a meta-analysis which demonstrated significant symptom relief and reduction of medication requirements. Immunotherapy has also been shown to be effective for mite-induced perennial AR and may also be effective in mold-induced rhinitis. The duration of treatment is generally 3 to 5 years, and symptomatic improvement continues for years after discontinuation.
Asthma
Many studies in the past decade have examined the efficacy of immunotherapy for allergic asthma. Certainly, allergic sensitization and subsequent allergen exposure contribute significantly to asthma morbidity in children, making immunotherapy an appealing option for children with allergic asthma. However, IgE-mediated mechanisms are only part of the underlying pathophysiology of asthma, making the rationale for immunotherapy as a treatment option in allergic asthma less straightforward.
Results of clinical trials examining the efficacy of immunotherapy in allergic asthma have been conflicting. To complicate matters further, many studies have not included placebo arms, making it difficult to draw any conclusions about efficacy from those studies. Abramson and colleagues conducted a meta-analysis of randomized, controlled trials for immunotherapy in asthma. Eighty-eight trials met inclusion criteria of being double blind, randomized and placebo controlled. After analysis of the combined results from these trials, immunotherapy was found to reduce bronchial hyperreactivity and medication use and to improve asthma symptoms. There was no clear effect of immunotherapy on pulmonary function.
A comprehensive review also concluded that immunotherapy is effective in the treatment of asthma but in carefully selected circumstances. The authors concluded that immunotherapy is effective in grass pollen asthma but that results from studies for ragweed asthma were inconclusive. In addition, mite immunotherapy with standardized extracts was effective in reducing symptoms and increasing the threshold dose of mite extract needed to induce bronchial obstruction in bronchial challenges. The authors also make the point that children receiving mite immunotherapy benefited to a greater extent than adults, and a recent study demonstrated that mite immunotherapy had a steroid-sparing effect in children with asthma.
Immunotherapy for animal-induced asthma has been more controversial. Some proponents of immunotherapy believe that there is a role for animal immunotherapy in the treatment of asthmatic patients who live with pets, but consensus statements from respected international organizations maintain that allergen avoidance is first-line therapy for these patients. There have been carefully conducted, placebo-controlled trials demonstrating the efficacy of specific immunotherapy for cat asthma. Studies have demonstrated a decrease in the quantitative airway responsiveness to cat allergen and decreased skin test reactivity in those treated with cat immunotherapy, but studies examining improvement in clinical symptoms have been inconclusive.
Clinical trials evaluating mold immunotherapy for asthma have been published for Alternaria and Cladosporium. One of the Cladosporium trials was conducted in children and demonstrated a decrease in allergen sensitivity on inhalation challenge, but did not provide good evidence of a decrease in symptoms or medication use. Some studies evaluating Alternaria immunotherapy have demonstrated an improvement in asthma symptoms and a decrease in medication use. Although there is evidence to support the addition of certain mold extracts to an immunotherapy prescription, more data are needed before any firm conclusions can be made about immunotherapy in mold asthma.
Although many studies support a role for immunotherapy in the treatment of allergic asthma, there have been some studies that have not demonstrated the efficacy of immunotherapy for asthma. One of these was a well-conducted, placebo-controlled trial of immunotherapy for children with allergic asthma, and the investigators found little evidence to support the efficacy of polyvalent (i.e. a mixture of extracts of various allergens) immunotherapy. Both the active treatment and placebo groups had a reduction in medication use and improvement in PD 20 FEV 1 , and the outcomes in the treatment group were not statistically significantly better than those in the placebo group. Despite the negative results of this well-conducted study, many other published studies have demonstrated the efficacy of immunotherapy for allergic asthma. One of the major differences in this trial is that multiple allergen extracts were included in the injections. Although this is the usual approach to immunotherapy for allergic asthma in the USA, European standards require therapy with a single allergen extract (e.g. dust mite, cat, Alternaria ), and this trial is the only one dealing with polyvalent immunotherapy. It is possible that this approach differs in some important way from immunotherapy with single-allergen extracts.
Stinging Insect
Immunotherapy for venom allergy is highly efficacious, affording protection for more than 95% of individuals undergoing treatment. Although venom immunotherapy is indicated in adults with evidence of IgE to Hymenoptera venom and a history of a systemic reaction to Hymenoptera, the indications in children are somewhat different. Studies of the natural history of venom allergy in children indicate that the risk of a serious reaction from a subsequent sting for a child with a history of a cutaneous systemic reaction is small. There is an approximately 10% incidence of subsequent systemic reactions in this patient population and a 0.4% incidence of more severe reactions involving the respiratory and cardiovascular systems. In light of these findings, venom immunotherapy has been reserved for those children who have had ‘life-threatening’ reactions to Hymenoptera as well as evidence of IgE to Hymenoptera venom (see also Chapter 57 ).
Food
Although oral and sublingual immunotherapy are not currently recommended treatments for food allergy, they are being actively investigated. Subcutaneous immunotherapy for foods has proved far too risky to pursue as a treatment option. More recently, several randomized controlled trials of oral immunotherapy (OIT) for several foods, including egg, milk, and peanut have been completed, and although their results have indicated that OIT is a promising treatment for IgE-mediated food allergy, there are some significant limitations that must be addressed before it can be recommended as a treatment. First, reactions are common and unpredictable, so methods for reducing and predicting risk are needed. Second, only approximately 30% of children on active treatment achieve sustained unresponsiveness, meaning that they can tolerate a full serving of the food after stopping OIT for a period of time, typically 1–6 weeks. The remaining children have therefore lost their desensitization, indicating that it was dependent on continued doses of OIT. A more detailed discussion of immunotherapy for food allergy can be found in Chapter 49 .
Practical Considerations
Patient Selection
Allergic Rhinitis
Immunotherapy should be considered for patients with clear evidence of IgE-mediated symptoms who have not been adequately controlled with first-line medical therapy, including antihistamines, nasal corticosteroids and ocular antihistamines or antiinflammatory medications. Other aspects of the patient’s history should be taken into consideration. For example, successful immunotherapy requires that a patient be able to visit a physician’s office weekly and spend a minimum of 30 minutes there. Certain medications, such as beta blockers, put a patient at higher risk for systemic reactions to immunotherapy.
Asthma
Although some of the same principles of patient selection apply, immunotherapy for asthma deserves separate commentary. As in AR, patients must have demonstrable IgE to allergens to which they are exposed and the clinical history should be consistent with exacerbation of asthma symptoms with exposure to the allergens. A patient’s ability to visit a medical facility weekly, as well as his or her medications and age, should be taken into consideration. Immunotherapy may be appropriate for treating asthma that has been difficult to control, but it should not be prescribed for patients with unstable asthma and an FEV 1 less than 70% of predicted, so it may be least appropriate for patients who continue to have clinical symptoms of asthma despite maximal medical therapy.
Allergen Extracts
Allergen Extracts for Immunotherapy
Allergen extracts are prepared by extracting bulk source materials (e.g. pollens, mite cultures, fungal cultures) in aqueous buffers; typically the potency of these extracts is expressed in a ratio of the weight of source material extracted to the extraction volume, such as 1 : 10 wt/v. Variations in the bulk sources and in the manufacturing process have led to vast differences in the quantity of active allergens in these extracts. A second approach to labeling is based on the total protein content of the extract and is expressed in protein nitrogen units (PNUs); this method has little relationship to allergenic potency but is still commonly used in the USA. Efforts to standardize extracts in Europe and the USA have produced fundamentally different approaches. One approach measures the content of the major allergen or allergens in the mixture using crossed immunoelectrophoresis, immunodiffusion, RAST inhibition or enzyme-linked immunosorbent assay. Another approach compares the biologic activity of the material with the diameter of a control intradermal injection of histamine and expresses this as a BU (biologic unit). The FDA uses a slightly different approach to establish a BU, in which the flare diameter of reference extract in a select group of allergic volunteers is compared with a reference extract, and expresses the result in allergen units (AU) or bioequivalent allergen units (BAU). The results are somewhat confusing, and most commercially available extracts are labeled with more than one method to try to simplify administration of the materials. Studies that have established guidelines for effective maintenance doses for particular allergens report these doses in micrograms of major allergen, but translating wt/v, PNU, BU, AU or BAU into microgram doses can be difficult. Fortunately, some products have also been standardized by the major allergen concentration expressed as micrograms per milliliter ( µg/mL). There are also some data translating allergen content into micrograms of major allergen; this information may be helpful in guiding dosing decisions. Table 23-1 is adapted from a recent comparison of labeling methods. Where they are available, standardized extracts should always be used for therapy.
