ABIM • PCCU

Lesson 3, Volume 12—Immunotherapy and Allergen Avoidance for Allergic Airway Disorders

By John W. Georgitis, MD, FCCP

Objectives

1. To list common categories and types of allergens
2. To describe early and late phase responses and importance of mast cells in the allergic response
3. To list the measures of allergen avoidance
4. To examine the benefits and risks of immunotherapy
5. To identify the advantages and disadvantages of immunotherapy in asthma.

Key words

airway disorders; allergen avoidance; allergen immunotherapy

Medical management of rhinitis and asthma have been reviewed recently, especially in the revised National Heart, Lung and Blood Institute Expert II Panel Report on asthma guidelines,¹ so this discussion will cover the indications and methodology of allergen avoidance and immunotherapy. Immunotherapy and allergen avoidance are highly successful for aeroallergen-induced allergic airway disorders, especially allergic rhinitis. Allergic airway diseases, rhinitis, and asthma are fairly common along with chronic disorders. Allergic rhinitis by conservative estimates affects at least 20% of the general population.² An additional 7 to 10% of people can develop allergic rhinitis over the years.³ Allergic rhinitis classically affects people in their peak productive years of 10 to 35 years but can affect infants and geriatric individuals. There is a high morbidity and cost associated with allergic rhinitis: $500 million per year in health-care costs, 2 million lost school days, 3.5 million lost work days, and 2.8 million days in restricted activity. Allergic rhinitis is also associated with other disorders such as chronic or recurrent sinusitis, acute and chronic otitis media, asthma, and atopic dermatitis. In fact, 20% of rhinitis patients also have concomitant asthma.

Asthma is thought to affect 5% of the population or 10 million of the US population. It is a far more serious disorder since mortality rates are rising nationally and internationally in select populations. Costs for treatment for asthma average $3.6 billion in 1990 for hospital and physician expenses and $1.1 billion in medications.⁴ The indirect expenses for asthma were $2.6 billion, which included lost school days and days absent from work. Allergic asthma is one of many triggers for asthma and may be the major cause for underlying bronchial hyperreactivity present in asthma. Of note, 60% of asthmatics also suffer with concurrent rhinitis symptoms.

The patient obviously must manifest symptoms after allergen exposure and have demonstrable allergen-specific IgE either by skin testing or serologic testing before instituting allergen avoidance or utilizing immunotherapy for the disorder. Allergen avoidance is not a 100% reduction of the aeroallergen exposure, but is in fact a reduction hopefully at levels below the threshold dose which initiates symptoms. Immunotherapy is best described as a slow immunization to a specific aeroallergen or allergens, yet has intrinsic risks associated with the treatments. Immunotherapy addresses the underlying allergic reaction and attempts to modify the response to aeroallergens that induce the reaction.

Aeroallergens include pollens, molds, and animal particles such as hair, saliva, dander, urine, feces, and body parts (mammals, mites, birds, insects). An aeroallergen must be sensitizing and must be present in the ambient air in ample quantities to cause symptoms in an allergic individual. Ragweed pollen is probably the most cited example of a seasonal aeroallergen in that people allergic to ragweed have significant exposure during the months of August and September. Examples of other seasonal allergens include grasses (late spring exposure); oak, birch, hickory, maple, walnut, cedar, willow (early spring); and Russian thistle, pigweed, plantain, chenopodium or sage (summer and fall). The most often-cited perennial allergens are house dust mites: Dermatophagoides farinae and Dermatophagoides pteronyssinus, yet cockroach antigen is also a prevalent allergen in inner-city housing complexes.

Pathophysiology of Allergic Reactions

The basic mechanism of the allergic response involves allergen-specific IgE, which is bound on the surface of mast cells^5,6 and which reacts to a specific aeroallergen resulting in cross-linkage of IgE receptors and subsequent mast cell activation. The mast cell is a keystone cell in this response. Other inflammatory cells such as neutrophils, basophils, and eosinophils are important in this reaction, but the mast cell is the first cell activated in the allergic reaction. Mast cells are located on the mucosal surface, interspersed among epithelial cells and in the submucosal space. With aeroallergen exposure and mast cell activation, preformed and newly formed mediators are released rapidly into the surrounding tissues. The preformed mediator, histamine, is found in high concentrations inside the mast cell and with release activates histamine receptors responsible for mucosal vasodilation, itching, edema, secretory gland, and goblet cell mucin release. Newly formed mediators are created in this allergic reaction from phospholipase A₂ activation resulting in arachidonic acid formation, which in turn is metabolized to leukotriene C4 or prostaglandin D₂.^6,7,8 In addition, platelet activating factor (PAF) is formed. Chemotactic factors and cytokines are also produced causing cellular influxes of neutrophils, eosinophils, and basophils to the site of the allergic reaction. This immediate response to aeroallergens involving mast cells is called the early allergic reaction.

Two to 8 hours later, there is another allergic reaction referred to as the late-phase reaction (LPR),⁹ which is characterized by an influx of inflammatory cells. Predominantly neutrophils and eosinophils appear at the site and there is further leukotriene and histamine release into nasal secretions during the LPR indicating alternative sources of these inflammatory mediators other than the mast cell. In addition, the tissues are hyper-responsive to other nonaeroallergen stimuli such as irritant gases, perfumes, or odors for example. In terms of reactivity, the tissues during the LPR also respond to lower doses of the aeroallergen than the first initial exposure.

During natural exposure to aeroallergens, the allergic individual exhibits a seasonal rise in allergen-specific IgE, eosinophilia of the tissues and secretions, hypersecretion, inflammation and increased hyperreactivity of the airway tissues.¹⁰ There is also an increase in histamine in nasal secretions and inflammatory mediators during the aeroallergen exposure.

Allergen Avoidance

Americans in the United States spend 30 to 60% of daily living in their homes, so reduction or control of allergen exposure at home should be the natural first intervention for treating allergic airway disorders. These interventions are simple and inexpensive compared to pharmacologic options. Yet actual institution of these controlling measures is dependent upon the individual's motivation. Analysis of home or work dust samples can characterize and quantitate the specific environmental allergens. Furthermore, postinterventional dust analyses may provide a measure of the specific intervention's effectiveness. Table 1 lists the common indoor allergens and known threshold levels for specific allergens. Tables 2-5 are specific interventions for identified allergens. Der f 1 and Der p 1 levels greater than 2,000 ng/g of dust collected and Fel d 1 higher than 8,000 ng/g delineate levels where there should be environmental intervention.^11,12

Recent studies have demonstrated that simple environmental intervention such as changing to new bedding, removal of an animal, regular vacuuming and dusting, or hot water washing of bedding and pillows can reduce the amount of specific allergens present in homes.^13,14 In terms of clinical efficacy, Ehnert and associates have shown that reduction of house dust mite levels below 2 ng/g of dust collected increases the PC₂₀ to histamine in asthmatic children.¹⁵ Other simple measures such as use of HEPA filters, which reduce dust amounts, result in symptomatic improvement in individual allergic subjects.¹⁶ Unfortunately, effective reduction in cockroach allergen has been difficult and requires further study.

Mechanisms of Immunotherapy

Several general principles are needed before instituting immunotherapy. IgE-mediated sensitivity should be documented to a specific aeroallergen by either cutaneous testing or by in vitro testing. There also needs to be an extract of the aeroallergen. Immunotherapy needs to be given in relatively high doses for a long period of time. The dose must be close to that dose that produces local and systemic reactions. A favorable response results in a reduction in symptoms, yet there is a fine line between effective dose and injections resulting in significant reactions. This is the major reason that allergen immunotherapy should be administered in an office setting.

Effective immunotherapy alters skin test response, basophil histamine release, release of mediators into nasal secretions during challenge, and bronchial reactivity. The favorable clinical effect is often seen before alteration of these immunologic findings. The clinical response is often associated with an increase in allergen-specific IgG identified as "blocking antibody." Although there are exceptions where some patients have a favorable response but no IgG antibody production. With immunotherapy, there is an initial rise in serum allergen-specific IgE, then blunting of the seasonal rise in IgE and ultimately a fall in IgE titers. Immunotherapy may also reduce mast cell sensitivity to aeroallergens independent of its effects on B cell production of IgE and IgG.

The rationale for immunotherapy is that in nature, avoidance of pollens, molds, and house dust mites is extremely difficult and unrealistic at times. Alternatively, some aeroallergens such as animal danders from dogs or cats and urine from laboratory animals can be avoided. The goal of immunotherapy is to increase the individual's tolerance to natural exposure of the aeroallergen resulting in symptom control and decrease in medication use.

Efficacy of immunotherapy for allergic rhinitis has been well documented.^17,18 In placebo-controlled trials, ragweed immunotherapy demonstrated efficacy based upon symptom-medication scores. This effect was dose-related whereby maintenance doses of 1 µg or more of antigen E (Amb a I) were effective and lower doses ranging from 0.00024 to 0.006 µg were ineffective. Immunologic findings were a rise in serum IgG, an initial rise in serum IgE then decline to pretreatment levels, no seasonal rise in IgE, an increase in ragweed-specific IgA and IgG in nasal secretions, a decrease in lymphocyte responsiveness to ragweed, an increase in threshold allergen dose on nasal challenge for release of inflammatory mediators (histamine, PGD₂, leukotrienes, and kinins) and suppression of late-phase skin reactions to intradermal ragweed extract. Similar double-blind studies have shown clinical efficacy for grass, mountain cedar, and house dust mite immunotherapy for allergic rhinitis.

Efficacy for allergic asthma is not as extensive as for rhinitis, inherent in identification of aeroallergen-induced asthma without other complicating factors. One study was unable to identify adequate numbers of patients to investigate ragweed immunotherapy in asthma.¹⁹ In grass-sensitive asthmatics given immunotherapy, older studies noted a reduction in symptoms with treatment. A recent study by Creticos and associates²⁰ involving ragweed-allergic asthmatic adults did show some benefit in asthma symptoms and medication use, yet Adkinson and colleagues²¹ were unable to show superiority of immunotherapy to conventional "appropriate medical treatment" in children with perennial asthma.

Cat-induced asthma has been the best model for allergic asthma. In elegant studies, cat immunotherapy was shown to be as safe as ragweed immunotherapy.^22,23 Double-blind trials using cat immunotherapy demonstrated a decrease in bronchial reactivity to cat dander, a reduction in skin prick test response, an increase in IgG to the major cat allergen, Fel d 1, and the expected response of an initial rise in IgE then fall to pretreatment levels. One study by Ohman and associates²³ used deliberate exposure to cats in a confined area to demonstrate that patients on active immunotherapy had a significant delay before onset of eye and pulmonary symptoms. Similar studies²⁴have shown efficacy for dog immunotherapy in asthma.

Immunotherapy to house dust-induced asthma has had conflicting results, with two positive studies and one negative study. This is not surprising since house dust contains a variety of allergens ranging from mites, cockroaches, cats, dogs, other animal danders to pollens and molds. Immunotherapy to house dust mite shows a significant decrease in asthma symptoms, decrease in medications, and decrease in response to both immediate and late-phase responses during bronchoprovocation.

There are, however, immunotherapy procedures that are not effective. Low dose regimens (Rinkel technique) are proven ineffective in several double-blind, placebo-controlled studies. Immunotherapy based upon provocation-neutralization and sublingual immunotherapy have not undergone the rigors of placebo-controlled, double-blind investigations as other immunotherapy regimens, so efficacy of these types is purely anecdotal.

Immunotherapy Regimens

There are certain basics to immunotherapy. In selecting patients, they need to have symptoms of allergic rhinitis or asthma, demonstrate IgE by skin testing or in vitro testing, and inability to control symptoms through avoidance and/or medications. Immunotherapy should be used with other general treatment regimens, ie, continuing asthma medications, and controlling their environment. A practical consideration is limiting the allergens to 6 to 10 for each treatment vial. Therefore, the testing should identify the selective aeroallergens to be used in the individual. Treatment with irrelevant allergens is not advised, wasteful, and may induce sensitivity to that allergen.

Allergenic extracts require careful storage in order to maintain potency. Extracts will lose 50% of their initial potency when kept at room temperature or by going through repeated freezing and thawing. Extracts containing 50% glycerin are stable for 3 years at 4^o C as are freeze-dried extracts kept at the same temperature. Concentrated aqueous extracts without glycerin stored at 4^o C lose their potency slowly over time such that it is at 50% potency after 6 months. Diluted aqueous extracts lose potency more rapidly. Use of standardized extracts is highly desirable and the FDA now utilizes the allergy unit (AU) to characterize these extracts. For other extracts, the old method for extracts utilizes protein nitrogen units (PNU) or weight per volume (w/v).

The recommended starting dose for sensitive patients is 0.5 AU, 0.4 PNU or 0.1 mL of a 1:200,000 w/v dilution. Doses may be safely increased by two-fold dilutions at weekly or twice a week intervals. If local or systemic reactions occur, the dose should be reduced to the previously tolerated dose. Rush or clustered schedules have been developed to expedite the immunization process but have not undergone extensive trials for aeroallergen use.

Maintenance dose is that concentration resulting in clinical reduction of symptoms and administered safely without systemic reactions. This is usually an individual response but most patients can achieve a dose of 1,000 AU with the exception of cat extract, which is 25,000 AU. The interval of maintenance dose is 3 to 4 weeks. Duration of therapy is dictated by the patient, but is commonly given for 2-3 years during which there is gradual clinical symptom control. Discontinuation of immunotherapy may be considered after this interval weighing the risk of reappearance of symptoms. In situations without clinical improvement, one must consider either modification of the immunotherapy or cessation of the regimen.

Most patients on immunotherapy will experience local reactions such as localized swelling and erythema that resolve over hours. However, local reactions can be large (>4 cm in diameter) causing considerable discomfort and lasting greater than 24 h. Systemic reactions are a distinct risk for patients on immunotherapy.²⁵These may range from simple hives to severe life-threatening anaphylaxis. In some instances, systemic reactions have been fatal.¹⁸ Systemic reactions may be generalized urticaria and/or angioedema, swelling of the airway (tongue, throat, and lower airway) with impaired swallowing or breathing, or cold, damp skin, rapid pulse, and low blood pressure. In addition, there may be exacerbation of allergic symptoms such as sneezing, rhinorrhea, nasal congestion, wheezing, coughing, and shortness of breath. These must be differentiated from the vasovagal reactions of low blood pressure with low heart rate.

The American Academy of Allergy and Immunology has published recommended guidelines for practitioners giving immunotherapy. These are listed in Table 6. In addition, some physicians observe highly allergic individuals for 25-30 min with each injection. For asthmatic patients, immunotherapy should be administered only if the patient's peak flow or FEV₁ is greater than 75% of their personal best. In addition, immunotherapy probably should not be administered to patients on chronic beta-blockers or having significant cardiovascular disease. In pregnant patients, immunotherapy should not be started and for those patients already on immunotherapy but not a maintenance dose, the current dose should be used until the pregnancy is completed.

Future of Immunotherapy

The future of immunotherapy is difficult to predict, but in the foreseeable future, the regimens and/or agents will be vastly different than they are today. Local nasal administration for immunotherapy has been tried and found to be effective in ragweed and grass-sensitive individuals. The advantages of such a program are that treatment can be given at home, it is relatively safe, and it is cost-effective. However, further studies are needed to elucidate the mechanism(s) of action and use of other aeroallergens. Recent work²⁶ has indicated that anti-cytokine or anti-IgE therapy may be highly effective in altering the allergic response and is undergoing clinical trials.

Summary

In summary, allergen avoidance is the first intervention used in the allergic individual, whereas immunotherapy is best given for patients who are unresponsive to avoidance/environmental control and pharmacotherapy management. Immunotherapy is proven effective for allergic rhinitis and allergic asthma. Therapy however involves 2-3 years and has inherent risks of anaphylaxis and local reactions that the patient needs to be made aware of before instituting the injections.

References

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2. Hagy GW, Settipane GA. Rhinitis. 2nd Ed. Providence, RI: Oceanside Publishing Inc. 1991

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6. Barnes PJ. Pathophysiology of allergic inflammation. In: Middleton EM Jr, Reed CE, Ellis EF, et al, eds. Allergy: principles and practice. St. Louis: CV Mosby Co. 1993; 243-66

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11. Hamilton RG, Chapman MD, Platts-Mills TAE, et al. House dust aeroallergen measurements in clinical practice: a guide to allergen-free home and work environments. Immunol Allergy Pract 1992; 14: 96-112

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15. Ehnert B, Lau-Schadendorf S, Weber A, et al. Reducing domestic exposure to house dust mite allergen reduces bronchial hyperreactivity in sensitive children with asthma. J Allergy Clin Immunol 1992; 90: 135-38

16. Reisman RE, Mauriello PM, Davis GB, et al. A double-blind study of the effectiveness of a high-efficiency particulate air (HEPA) filter in patients with perennial allergic rhinitis and asthma. J Allergy Clin Immunol 1990; 85: 1050-57

17. Rocklin RE, Sheffer AL, Greineder DK, et al. Generation of antigen-specific suppressor cells during allergy desensitization. N Engl J Med 1980; 302: 1213-19

18. Norman PS. Safety of allergen immunotherapy. J Allergy Clin Immunol 1989; 84: 438-89

19. Bruce CA, Norman PS, Rosenthal RR, et al. The role of ragweed pollen in autumnal asthma. J Allergy Clin Immunol 1977; 59: 449-59

20. Creticos PS, Reed CE, Norman PS, et al. Ragweed immunotherapy in adult asthma. N Engl J Med 1996; 334: 501-06

21. Adkinson NF, Jr, Eggleston PA, Eney D, et al. A controlled trial of immunotherapy for asthma in allergic children. N Engl J Med 1997; 336: 324-31

22. Taylor WW, Ohman JL, Lowell TC. Immunotherapy in cat-induced asthma. Double-blind trial with evaluation of bronchial responses to cat allergen and histamine. J Allergy Clin Immunol 1978; 61: 283-87

23. Ohman JL, Findlay SR, Leiterman M. Immunotherapy in cat-induced asthma. Double-blind trial with evaluation of in vivo and in vitro responses. J Allergy Clin Immunol 1984; 74: 230-39

24. Valovirta E, Koivikko A, Vanto T, et al. Immunotherapy in allergy to dog: a double-blind clinical study. Ann Allergy 1984; 53:85

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26. Kepron W, Jackson C-J, Ceton HA. A canine model for the study of hapten-specific suppression of IgE-mediated bronchoconstriction and anaphylaxis. Int Arch Allergy Immunol 1987; 82:468-70

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