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-IgE-mediated disease, such as chronic nonallergic rhinitis or vasomotor 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 35 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 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

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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 immuno-therapy injections significantly reduced the rate of systemic 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 admin ister 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 IgE 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.

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