Allergic Disorders: When Should You Consider Immunotherapy?

Allergic disorders are becoming more common. For example, about 20% of Americans have allergic rhinitis, which accounts for more than 10 million office visits each year.¹ Most of these visits are to primary care clinicians.

Which of your patients who have allergic disorders are likely to benefit from immunotherapy? Here we discuss the indications and the contraindications; we also describe various schedules and routes of administration.

IMMUNOTHERAPY: AN OVERVIEW
Allergen immunotherapy involves the administration of escalating doses of a substance to which a patient is allergic. The goal of this technique—also known as desensitization, hyposensitization, and allergen vaccination—is to eliminate or decrease the severity of symptoms on future exposure. The proposed mechanisms by which immunotherapy achieves this effect are described in the Box.

The history of this practice dates back to 1900, when an oral route of pollen immunotherapy was proposed.² The more widely used subcutaneous route of administration was introduced in 1911.³

A large body of evidence has substantiated the efficacy of immunotherapy. Benefits include a reduction in allergy symptom scores and allergy medication use and a modification in the natural course of allergic disease. Immunotherapy may also prevent the development or progression of multiple allergies. Guidelines have been developed and recently updated for the use of immunotherapy in patients with venom allergy, allergic rhinitis, or allergic asthma.⁴ Allergens for which immunotherapy is effective include Hymenoptera venom, pollens, cat dander, dust mites, cockroach, and fungi.

Subcutaneous injection immunotherapy. The principal technique for administering allergen immunotherapy is via subcutaneous injections. In this process, patients are given gradually increasing amounts of an extract of the substance or substances to which they are allergic. The interval between injections may vary greatly. The type of allergen being administered, severity of symptoms, and wishes of the patient all play a role in determining the schedule.

A standard immunotherapy regimen entails injections of increasing concentrations of allergens once or twice weekly during a buildup phase. The starting dose is usually a 1000- to 10,000-fold dilution of the therapeutic dose—that is, a concentration generally agreed to be therapeutic for each allergen included in the vaccine. Over the course of 4 to 6 months, the dose of antigen increases until the therapeutic dose is achieved. This therapeutic dose is used as the maintenance dose. Some patients may not tolerate the projected dose; the maintenance dose in these cases becomes the highest tolerated dose. Maintenance dosing is continued monthly for 3 to 5 years.⁴

Expedited, or rush, schedules have been developed. The major benefits of rush immunotherapy are less time spent during the buildup phase, earlier clinical benefit, fewer physician visits, and decreased cost to the patient (eg, office visit copayments). Several such schedules have been formulated. Time to maintenance dosing ranges from 90 minutes⁵ to several days.

These benefits do not come without risks, however. Rates of systemic reactions as high as 55% have been reported with rush and ultrarush schedules.⁶ Therefore, premedication is typically recommended with rush immunotherapy. A typical regimen shown to decrease the incidence of systemic reactions includes prednisone and H₁ and H₂ antihistamines.^7,8 The addition of a leukotriene receptor antagonist is optional.

Cluster schedules are another way to expedite the time to maintenance dosing. This involves giving multiple injections per visit once or twice weekly. Thus, the buildup phase is shortened to 2 to 4 weeks. Rates of adverse reactions are significantly lower with cluster desensitization than with rush schedules.⁹

Sublingual immunotherapy. Although subcutaneous injection immunotherapy is used most frequently, other routes of administration have been proposed. Topical delivery of antigen via bronchial, intranasal, oral, and sublingual approaches has been evaluated. Among these alternatives, sublingual immunotherapy is the most popular. It is currently approved by the European Association of Allergy and Clinical Immunology and the World Health Organization as an alternative to injection immunotherapy. With this technique, the patient takes specific allergens in the form of quick-dissolve tablets, spray, or drops held under the tongue for 1 to 2 minutes, then swallowed. Doses are given daily during the buildup phase, which typically lasts 4 to 6 weeks.^10,11

This method of providing allergy desensitization is attractive for several reasons. It is conducive to home administration of extracts, which obviates the need for frequent office visits, and the discomfort of injections is avoided. The feature of sublingual immunotherapy that has drawn the most attention, however, is its excellent safety profile. A review of more than 20 studies found no serious systemic adverse events.¹² In a recent report, 16 serious adverse events were identified in 3984 patients given more than 1 million doses.¹³ No deaths have been attributed to sublingual therapy. However, because the efficacy of this method has yet to be established in rigorous trials, it is limited to investigational use in the United States. Also, because the dose of allergen used is typically significantly higher than maintenance doses in subcutaneous immunotherapy, the cost of the therapy may be higher, despite elimination of frequent office visits.

WHEN IS IMMUNOTHERAPY USEFUL?
A general approach to the patient with an allergic disorder is outlined in the Algorithm.

Venom sensitivity. The primary indication for immunotherapy is stinging insect venom hypersensitivity. An allergy evaluation is warranted in any patient who has had a systemic adverse reaction to an insect sting. If corresponding IgE antibodies are documented by means of positive results on skin tests or measurement of venom-specific IgE antibodies in blood, venom immunotherapy should be seriously considered.⁴ This recommendation applies also to fire ant allergy. Evidence suggests that patients younger than 16 years who have systemic reactions that involve only the skin (eg, urticaria or angioedema distant from the site of the sting) may not need desensitization.¹⁴ Venom immunotherapy should be continued for 3 to 5 years, which will provide protection against anaphylaxis should the patient be stung again.

Allergic rhinitis. Immunotherapy is the only therapy that modifies the natural history of allergic rhinitis, rather than merely alleviating symptoms. Substantial evidence supports the efficacy of immunotherapy in allergic rhinitis.¹⁵ Suitable candidates are persons with rhinitis and/or conjunctivitis symptoms attributable to IgE-mediated mechanisms.

Desensitization may be recommended for patients who do not achieve adequate control of symptoms with maximal medical therapy and avoidance measures, who cannot avoid triggers, or who experience intolerable adverse effects from medication. Other potential candidates include those who require long-term medication (at least 4 months per year) or increasing amounts of medication for symptom control.¹⁶ Some patients find the prospect of lifelong daily medication use unacceptable, and they may instead choose immunotherapy.

Identification of the allergens that provoke symptoms helps guide therapy. This is accomplished through a detailed history taking and skin testing based on the aeroallergens in the patient's locale, which generally include pollens of trees, weeds, and grasses; fungi; animal dander; and insects. In vitro testing can also be used to identify culprit allergens.

Allergic asthma. Patients with allergic asthma may wish to consider immunotherapy, although evidence for the efficacy of immunotherapy in allergic asthma is not as solid as the evidence in venom immunotherapy and allergic rhinitis.^17-19 However, adults with both allergic asthma and rhinitis are excellent candidates for immunotherapy. In children, evidence suggests that such treatment, when given for allergic rhinitis, may prevent the development of asthma.^20-22 Moreover, immunotherapy may reduce the development of sensitivity to other allergens.^23,24

CONTRAINDICATIONS
There are few absolute contraindications to desensitization. Many of the deaths attributable to immunotherapy have occurred in patients with uncontrolled asthma.^25-27 Immunotherapy is therefore contraindicated in a patient with severe, poorly controlled asthma. Injections should also be withheld from patients who are experiencing an exacerbation of asthma symptoms. This is ascertained via patient symptom reporting and peak flow measurement.

All patients should also be questioned about medication use before each injection. Evidence suggests that persons taking ß-blockers may be resistant to standard treatment with adrenergic agents if they have an adverse systemic reaction to immunotherapy.^28,29 Therefore, the use of ocular as well as oral ß-blockers is a relative contraindication to immunotherapy. In patients who cannot discontinue adrenergic blocking medications, serious thought must be given to the risks versus benefits of initiating or continuing desensitization. A recent study suggests that patients with severe cardiovascular disease do well if ß-blockers are continued during immunotherapy.³⁰

Other relative contraindications to immunotherapy include the use of angiotensin-converting enzyme inhibitors and any comorbid condition (eg, hypertension or unstable angina) that is poorly controlled.

PRECAUTIONS
Although it is preferable for patients to receive immunotherapy injections in the office of the physician who has prescribed and prepared the vaccine, there are times when it is acceptable to receive them elsewhere, usually in another physician's office. The location must have appropriate personnel and equipment for treating anaphylaxis, including respiratory and circulatory failure, should it occur. There must also be excellent communication between the allergist's and the administering physician's offices. This includes instructions for dose adjustment in case of interruption in the schedule and information about new vials, season of high allergen exposure, reactions to previous injections, and suboptimal general medical condition at the time the injection is to be given.

General precautions. Before each injection, patients should be evaluated for factors that might increase the risk of an adverse reaction. These include exacerbation of asthma symptoms, use of ß-blockers, and recent deterioration in other major medical comorbidities. If a significant risk factor is identified, it may be necessary to withhold the injection. After each dose is given, patients should remain under the supervision of trained medical personnel for 20 to 30 minutes. Studies have indicated that most severe systemic reactions occur within 30 minutes of injection. It is also useful to have patients carry injectable epinephrine on immunotherapy days and to be trained in its use in case of a delayed adverse reaction.

Although patients may find it convenient, home administration of allergen immunotherapy can rarely be justified. The absence of trained medical personnel, appropriate equipment for treating reactions, and strict documentation confers unnecessary risk.

Immunotherapy has not been shown safe for treating food allergy.^31,32 This is an active area of current research but is not yet standard practice.