Plant Antigens (Pollen)

Pollen is the male germinal element of plant flora emitted during the reproductive phase. Such plants can be pollinated by the wind, known as anemophilous, or by insect transfer of heavier, stickier pollen, known as entomophilous. Most clinically significant pollens (mainly anemophilous) share certain characteristics that promote their clinical antigenicity, and are said to satisfy the elements of Thommen’s postulates listed in Box 2.2. Even though entomophilous plants do not produce light, buoyant, windborne pollen, some may still be clinically significant if the patient handles the pollen from the plant, or with a massive, direct exposure. Of the thousands of continental anemophilous plants, only a little over 100 appear to be clinically prominent. Due to climate, natural selection, and human management of the environment, numerous pollen and mold zones exist around the world. Up-to-date zonal pollen and mold information is available through the Internet, the printed literature, and through antigen extract and allergy testing device vendors. While university extension divisions can also be queried in narrowing the number of pollinating plant species of antigenic and clinical importance, this approach may be of limited utility. Box 2.3 demonstrates a collection of suggested antigens, including pollens by family that can be used for objective testing and screening purposes. Antigenic plants are generally classified as trees, grasses, or weeds.

Animal Antigens

Fungi – Yeast and Molds

The fungi may be antigenically important as inhalants, ingestants, or contactants. While fungi include yeasts and molds, they are referred to in this section globally as molds. Mold allergies may be perennial or seasonal, indoor or outdoor. In theory, molds may elicit a Gell-Coombs I (allergic) or IV (delayed) response. In the central USA, for example, mold activity is perennial outdoors, especially if the winter is warm. There are seasonal flares in the spring, with the return of warmer and rainy conditions; in mid to late summer with increased humidity and heat; and in the moderate warmth of fall, with the decay of foliage and the priming of the weed season. Indoors, mold is promoted by dampness, warmth, darkness, and any moist, organic material used as a source of nutrients. Although many tens of thousands of species are known, less than 100 are of allergenic significance. Clinically important molds are noted in Box 2.7. Four of the most common mold species found indoor/outdoor are Alternaria, Penicillium, Aspergillus, and Cladosporium. In addition, mold families that are clinically important in allergic fungal sinusitis (AFS) may differ from those involved in rhinitis. Box 2.8 demonstrates a list of molds often reported in cases of AFS. There is little cross-reactivity between mold families. The major molds in any one locale will be important in the evaluation of not only rhinitis, but also asthma. Buoyant mold spores, measuring up to 20 μm, are a common form of inhalant mold exposure, in addition to mycelial forms and yeasts, which may be contactants and/or ingestants as well. Mold spores may be transported over long distances by the wind, and are of higher concentration in the cool of the evening and during warm windy weather after precipitation. While 8–12 molds are often sufficient for testing, in the highly mold sensitive patient, the difficult to diagnose patient, or the patient who is not doing well under treatment due to a suspected unidentified mold, a more expanded mold test battery may be indicated. At times, it has been worthwhile setting out mold spore collection plates obtained from some extract vendors to identify the prevalent species in the difficult patient’s environment.

Ingestants

Nonfixed food allergy

Food allergy may be rarely fixed, but is more commonly acquired in nature. Acquired food allergy is demonstrated in a susceptible individual, who begins to develop symptoms after repeated ingestion of a food. A current model for describing the conduct of this phenomenon is the cyclic nature of food allergy (Figure 2.2). In this model, after introduction and sensitization to the food, the patient begins to have symptoms with further ingestion of the food. If the ingestions are separated by intervals of time of several days or more, the symptoms may be easily identified with the ingestion. If the ingestions are very frequent, say daily, the symptoms may be more muted, diffuse and systemic, and more difficult to associate with the ingestion. Through elimination of the offending food, symptoms eventually improve/resolve, and in a period of months, the patient may become tolerant to the ingestion of the food. Tolerance may be maintained with infrequent ingestions, whereas the patient may cycle back to symptomatic expression if the interval of ingestion becomes more frequent. Fixed food allergy is always symptomatic and not affected by periods of abstinence from the food. Symptoms for peanut, seafood, and tree nuts generally do not improve with cessation and time.

Figure 2.2 Cyclic food wheel.

Positive epicutaneous skin testing for food is often inaccurate, although negative epicutaneous tests may have better predictive ability. There is some controversy over the efficacy of in vitro methods for food testing, with IgG food testing only relevant for ingestion, not hypersensitivity. When feasible, any possible food allergen, identified by history or positive in vivo or in vitro test, should have its clinical significance determined by elimination over a period of 1–2 weeks resulting in improvement of symptoms, or the elimination for 5–7 days and the demonstration of symptoms with reintroduction over a 2-day period. Suspected fixed food allergies should not be challenged, and strict avoidance of those foods should be recommended. The other option, and the gold standard, for cyclic food allergy is the use of the double-blinded, placebo-controlled food challenge. This challenge also requires an elimination of the food to be tested for 1–2 weeks before the challenge.¹⁹

Injectants

Allergic reaction by injection of allergenic material usually falls within the realm of drug allergy. Patient histories on occasion have indicated that oral ingestion of an allergen may not produce the reaction experienced with the injection of the drug. This observation is of limited clinical interest, since any true allergy to a drug by one route of exposure mandates avoidance of the use of that drug. Once again, some injectables have other nonactive ingredients which may be the provoking agent. Other injecting allergens may be via the puncture or sting of plants or animals. Reactions may be local, self-limited irritating responses, or delayed, more widespread immune responses, or an overwhelming systemic, IgE-mediated anaphylaxis. Allergic reactions to the stinging order of Hymenoptera (vespids and bees) are perhaps most important, followed by reactions to the fire ant. Distinction has to be made between a local reaction at the sting site versus a true allergic, more systemic or anaphylactic reaction. Desensitization in many cases is possible and indicated.²¹ Insect allergy is discussed in detail in Chapter 9.

Contactants

Boguniewicz and Beltrani²² estimate there are 85000 chemicals which will cause an irritant type of reaction to the skin upon contact. These irritant responses are nonimmunologic, usually cytotoxic. Approximately 2800 of these chemicals are capable of a delayed, Gell-Coombs type IV response, the mechanism of allergic contact dermatitis (ACD). Photocontact dermatitis is similar to ACD except that ultraviolet light is needed as part of the triggering mechanism. Irritants may include soaps and other cleaning agents, petroleum products, paint and printing chemicals, adhesives and synthetic resins, hair products, landscaping and pest control chemicals, building and insulating materials, and common allergens such as dust, plants, foods, and insects. Contact allergens include plants such as poison ivy or ragweed, metals such as nickel, plastic resins, organic dyes, preservatives, topical medications such as neomycin, and rubber chemicals including latex. These agents are often tested with patch testing, which is discussed later in this chapter. Identification and avoidance is the treatment of choice, augmented with topical and systemic medication.²²

Cross-reactivity

Cross-reactivity between antigens occurs when an antibody directed against one specific antigen is successful in binding with another, different antigen. The two antigens in question have similar three-dimensional structural regions, known as epitopes, which allow the antibody for one antigen to recognize a second antigen as being structurally the same antigen. Cross-reactivity may be robust among antigens of similar phylogeny such as different types of oak trees or ragweeds. Seemingly different antigens within families may substantially cross-react, such as with timothy and rye grass, or there may be a weaker cross-reactivity, such as with timothy and Johnson grass. Foods may also cross-react with other foods such as within the families of grains. Foods may cross-react with inhalants as in the oral allergy syndrome described later. Other associations described have included ragweed and some melons or bananas for example.²³ Patients may be more symptomatic during ragweed season when consuming cantaloupe, adding to their critical allergic load. This last example has been called concomitant food sensitivity. Latex represents an example of a collage of antigens to which some latex-sensitive individuals have reported a significant incidence of concomitant food sensitivity. Food cross-reactivities are not well understood and there has been a recent change in their emphasis. Knowledge of cross-reactivity allows for better management of allergic load, and the use of fewer antigens in objective testing and immunotherapy.

Screening

Screening for specific allergens is important conceptually and is often implemented as a first step in objective testing. Any skin testing method may be used, taking into consideration the sensitivity and specificity characteristics of the method chosen in interpreting the meaning of the screen results. The number of specific antigen skin tests used is kept low, usually 8–15 for economy. Antigens are chosen by history, significant local prevalence, high potency as an allergen, and good cross-reactivity potential. Based on the history and geographic area, select antigens for particular seasons, animal exposures, indoor symptoms, and so on, are chosen. The screen may consist, for example, of two potent, non-cross-reacting fall weeds such as short ragweed and chenopodium, one or two dust mites, cockroach, timothy and Bermuda grass, cat (always cat due to its ubiquitous presence and potency), some molds such as Alternaria, Aspergillus, or Cladosporium, and a few trees such as oak, cottonwood, or maple. A positive test(s) on the screen is an indication for further, expanded testing, unless the screen results alone are sufficient to direct management. Although a good allergic history can be regarded as an excellent predictor of the patient’s allergies, studies suggest that the history may be incomplete or inaccurate. A positive screen, therefore, may lead to additional testing and some unexpected positives. On the other hand, if the screen is negative, and yet the history is compelling for allergy, further testing may still be indicated.

Scratch Testing

The scratch test, as its name implies, involves scratching the superficial, keratin layer of the skin with a sharp instrument. This scratch may be performed through a drop of concentrated antigen extract placed on the skin, or the antigen may be applied to the area after the scratch. The site is observed for 10–20 minutes and the wheal and flare of any reaction is subjectively graded. The results are compared with positive and negative controls. The positive control is usually histamine, and the negative control is usually saline or diluent. For a test to be considered truly positive, the skin must be reactive to a positive control, usually histamine. Unfortunately there is frequently a high incidence of false positive results with scratch testing. The trauma of the scratch on occasion can stimulate a histamine-related axonal reflex, resulting in an axonal driven wheal and flare at nearby test sites (false positives). In addition, there is a significant occurrence of insufficient antigen penetrating the subkeratin layer to elicit a positive response in a truly allergic patient (false negative).^31–33 Thus, the scratch test has been considered unreliable in the diagnosis of allergy by the American Medical Association Council on Scientific Affairs due to its lack of sensitivity (false negatives) and specificity (false positives).³⁴ This safe but unreliable qualitative test, once widely performed, is not in common use today.

Prick/Puncture Test

The skin prick or puncture test (SPT), also known as an epicutaneous or percutaneous test, is the most commonly used methodology for allergy testing worldwide. This form of testing can be less sensitive, but is more specific than intradermal testing. For this reason, a negative SPT in a patient with a strong historical suspicion for allergy to that specific allergen usually warrants an intradermal test for that allergen. In this setting, it would make sense to challenge the skin with a more sensitive test for diagnosis. This progression is also wiser, in that epicutaneous tests are generally safer than fixed intradermal tests (FIT). While the concentration of antigen delivered with SPT is greater than that of FIT, the interface with the body is more superficial and some of that volume may be wiped away if an early reaction occurs. With FIT, the concentration of antigen is smaller, but with the increased volume delivered at a deeper level in the skin, the risk of reaction is greater. Progressing to FIT with a negative SPT would generally be more conservative and in line with safety.

SPT may be performed in one of two ways. The “drop and puncture” method involves applying antigen extract to the skin first and then puncturing the skin through the droplet.^31,33,35 The volar surface of the forearm is usually chosen as the site for the test, although the upper arm and the back can also be used for testing. With the SPT being performed initially on the arm, management or adverse systemic reactions may be facilitated by using a tourniquet on the arm above the site of the test. Therefore, the SPT is usually performed on the forearm and the FIT on the upper arm or back. The antigen used is usually a standardized concentrate or a nonstandardized concentrate of 1 : 10 or 1 : 20 w/v. The positive and negative controls are histamine and a diluent such as buffered, phenolated saline respectively. After alcohol cleansing and drying the volar surface of the forearm, areas at least 2 cm apart are marked. This distance between test sites will potentially avoid vigorous wheal and flare responses from running into each other as well as making an axonal response less likely. A drop of a different specific antigen, determined by the history, is placed at each mark. Using one of several single puncture devices available, the skin is punctured through the droplet to a superficial level without producing a show of blood (Figure 2.3). The device is discarded. As recommended by OSHA, the puncture and wipe technique should not be currently used because of the bodily fluid/pathogen contamination risk to the technician and the possibility of cross-contamination of antigens. There are numerous single puncture instruments to choose from. Some of these include: the Duotip-Test® and Duotip-Test®II (Lincoln Diagnostics, Decatur, IL), Sharp-Test™ (Panatrex, Inc., Placentia, CA), Morrow Brown® (Alkaline Corp., Oakhurst, NJ), Quintip® (Hollister-Steir Labs, Spokane, WA), GreerPick™ System (Greer Laboratories, Inc., Lenoir, NC), and AccuSet™ (ALK-Abelló, Round Rock, TX).

Figure 2.3 Single-prick skin testing device.

The “dip and puncture” method allows test site preparation in the same fashion as above.^31,33,35 After marking the arm, the puncture device tip is dipped into a well with the concentrate of the specific antigen to be tested, and then the “loaded” device is applied to the test site. As with single prick testing, there are several multiple puncture devices available to apply more than one antigen simultaneously. Some of these devices and their manufacturers are: Multi-Test and Multi-Test®II (Lincoln Diagnostics, Decatur, IL), Quick-Test (Pantarex, Inc., Placentia, CA), Quin-Test® (Hollister-Steir, Spokane, WA), and Skintestor Omni™ (Greer Laboratories, Inc., Lenoir, NC). As an example, the Multi-Test®II device has two rows of four puncture heads in parallel (Figure 2.4). The plastic points of each head are 1.9 mm in length and hold the antigen after placement, until it is deposited into the epithelial/superficial dermal layers of the skin, for a total of eight tests per application. The firm but gentle pressure of the application, followed by a gentle rolling motion delivers a test comparable to a superficial intradermal test. Multiple puncture devices are safe, reproducible, and reliable, and may be used effectively as a screening test modality.^31,36,37 Multiple puncture devices deliver more tests per unit time, and are cost-effective and well tolerated by patients.

Figure 2.4 Multi-prick skin testing device.

Interpretation of SPT can utilize a subjective grading system or can involve precise measurement of wheal size. Tests are usually read in 15–20 minutes and area compared to positive and negative controls (Figure 2.5). Pseudopodia and irregular spreading are noted. Wheal sizes of 3 mm or greater than a negative control are generally considered positive. In another approach, SPT results can be given a score of 0 to 4+ based on size, amount of erythema, and presence of pseudopodia. While SPT testing is becoming more uniform, the scoring systems are still varied.^31,33,35

Figure 2.5 Multiple prick tests on patient’s arm.

A nuance in testing is the use of SPT in the evaluation of oral allergy syndrome (OAS). The technique has been called the prick + prick method, an attempt to use fresh, unprocessed antigen in the epicutaneous test format. Pastorello has described OAS as a complex of signs and symptoms exclusively involving the oral and pharyngeal mucosa subsequent to contact with a specific food.^38–41 The foods involved are usually either a fresh fruit, nut, or fresh vegetable. There is almost always an association with an inhalant, most commonly a pollen. The presentation may be as minor as tingling in the mouth or as threatening as laryngopharyngeal edema with airway obstruction. The suspected relationship is a cross-reactivity between the food and the pollen. When the food is ingested, often during the pollen season, the syndrome is triggered.⁴² As an example, OAS has been demonstrated with silver birch and hazelnut.⁴³

In evaluating this syndrome from an objective testing standpoint, there are problems with false negatives for both in vivo and in vitro techniques. It is suspected that there is a degree of physical lability of the functional immunogenic makeup of the antigens involved which makes detection difficult.⁴⁴ For testing purposes, antigenic material has to be processed in some way. Antigens are processed to be made into allergenic extracts and they are processed to be attached to a substrate for an in vitro test. Even the food used for the double-blind, placebo-controlled food challenge has to be lyophilized, and there is a problem as well with gastric acid altering the processed food antigen(s).^43,45 It is suspected that during the processing, the antigenic nature of the epitopes involved is changed enough such that the testing results in cases of truly positive patients are inconsistent. As such, some in vitro and in vivo testing methods using fresh, unprocessed antigenic material have shown some promise.^36,46,47 One attempt is a prick + prick method. As an example, a fresh fruit being tested is punctured by the pricking device which hopefully loads the device with workable antigenic material. Immediately the skin of the patient is then pricked with the loaded device. While results using this method have shown somewhat better correlation of history with objective testing, less than optimal sensitivity still makes testing for OAS problematic. OAS represents a form of concomitant sensitivity and has been referred to as clustering of hypersensitivity.⁴⁸

Single-dilution (Fixed-dilution) Intradermal Test

Epicutaneous tests such as SPT are often utilized as screening tests for allergy. They may be used in a screening battery, and in the traditional sense of allergy testing, as a safe first step in the testing sequence. If the SPT is negative for a particular antigen, and the history suggests presence of allergy to that antigen, it may be indicated to perform an intracutaneous or intradermal skin test for diagnosis. Intradermal tests are generally more sensitive than epicutaneous tests. They also have a higher risk of adverse reactions. It is therefore essential to demonstrate the absence of severe reactivity with a negative SPT first, or to use a dilutional intradermal method such as IDT, or a blended test such as modified quantitative test (MQT). In performing FIT, the concentration is usually 1 : 100 to 1 : 1000 of that concentration used for the negative SPT. This test should not be used for food testing because of the incidence of false positives and the risk of a systemic reaction in a highly allergic patient.³⁵ The test is performed by injecting just enough test antigen (usually 0.02 mL) under the superficial epithelial layer of the skin (intradermal) to raise a 1- to 3-mm skin wheal. This is done with a tuberculin syringe, bevel down, at an approximately 45 degree angle. The test is read and scored in a similar manner as with SPT.³⁵ With the traditional sequencing of SPT and FIT, highly sensitive (+SPT) and relatively lower sensitive (−SPT, +FIT) patients may be detected.

If a patient is going to be treated with environmental control (EC) and symptomatic medication, there has been some controversy as to the utility and accuracy of the single-dilution intradermal test.³¹ The use of SPT and FIT for diagnosis and the institution of immunotherapy, however, has been successfully practiced by allergists for many years. One specific issue of concern is diagnostically overlooking the patient with very low sensitivity to the antigen being tested. This failure to diagnosis low-level allergy may be a factor leading to less than optimal results with diagnosis and immunotherapy since the risk of undertreatment is higher. This issue led to the development of dilutional techniques such as IDT and MQT.

Intradermal Dilutional Test

Intradermal dilutional testing (IDT) is a skin testing method using a series of 1 to 6 dilutions of a test antigen concentrate, applied in sequence from dilute to more concentrated, until an endpoint determining diagnostic reactivity is obtained. This method is both qualitative and quantitative. IDT has been approved by the AMA Council on Scientific Affairs for the diagnosis of allergy and, when indicated, the initiation of immunotherapy.³⁴ This method is safe, and does not require a preceding epicutaneous test. Other benefits of IDT include an improvement and standardization of test interpretation, reproducibility and standardization of testing procedure, and due to its functioning as a quantitative bioassay, a method for allowing safety with variations in antigen sourcing and single antigen extracts. The following explains the method. The reader is referred to other references for even more extensive details and nuances which are beyond the volume of this chapter.^31,32

Antigen preparation for IDT testing is important. Extract concentrates formulated by the vendor in the weight/volume (w/v) format should be 1 : 20 w/v or converted to 1 : 20 if supplied as 1 : 10 w/v by diluting 1 to 2 with a buffered, phenolated saline diluent (diluent). Antigens supplied as standardized extracts are usually considered conceptually as 1 : 20 dilutions, although local practices for individual antigens may differ. The panel of six dilutions for each specific antigen needed for the testing will be made starting with six, 5-mL, sterile injection stoppered bottles filled with 4 mL of diluent. One milliliter of the concentrate is then injected and mixed with the diluent filled bottle labeled #1 dilution. This now becomes a 1 to 5 dilution of the concentrate designated for mixing the testing dilutions. The #2 dilution is then mixed in a similar manner taking 1 mL of the #1 dilution and mixing it with the 4 mL of the next diluent filled bottle, labeled #2 dilution (1/25 of the concentrate). This process is repeated until the #6 dilution (1/312 500 of the concentrate) is made. It is rare that dilutions weaker than a #6 dilution will be needed for testing or mixing antigen for immunotherapy. Extracts from the vendor will have glycerin in them to preserve potency. Glycerin, as an irritant, can be a nonallergenic trigger for a whealing response and will need to be used as one of the three controls for the testing method. The glycerin control results will be taken into consideration when evaluating IDT results for the more concentrate dilutions (higher glycerin content from the concentrate). The other two controls will be histamine and the phenolated saline diluent. These controls will help rule out a suppressed reactive state (anergy or medication suppression [e.g., antihistamine, tricyclic antidepressant] = negative histamine control) or a hyperreactive state (e.g., dermatographia = positive histamine, glycerin, and diluent control). Rarely a patient will react to the phenol in the diluent in which case the diluent control will be positive.³¹ With six-bottle series of dilutions for each antigen, the clinician is ready to perform IDT.

The upper outer, hairless surface of the arm is prepped with alcohol and dried, then marked horizontally at the arm’s top, left to right, 6 to 1, with 2 cm between marks (helps prevent axonal responses). Then, vertically down, below and left of the #6 mark, the arm is labeled for the antigens to be tested, again 2 cm spaced. After the controls are placed and a response indicating the patient’s appropriate state for testing established (refer to reference 31), specific antigen testing begins with an array of intradermal tests for the #6 dilution of all of the different antigens to be tested. This amounts to a vertically placed row of tests below the #6 mark and to the right of the respective antigen labeling (Figure 2.6). The technique for placing the test is as described before, except enough antigen volume is drawn into the testing syringe to produce a 4-mm skin wheal. Since this usually requires an injected volume of about 0.02 mL of antigen, accomplishing the 4-mm wheal comes from trial and error experience rather than trying to allocate 0.02 mL by a measured injection. The tests are observed for 10–20 minutes, after which the diameter of the wheal is measured, neglecting the erythema which may accompany it. A negative whealing response will be 5 mm, starting with the 4-mm bleb at the time of the intradermal injection, which grows to 5 mm due to nonallergic factors. If an initial test at the #6 dilution is negative, another test using the #5 dilution is placed in the appropriate column, and so on, until all the dilutions are shown to be negative or until a positive response occurs. A positive response will be a wheal size greater than the 5 mm. A positive allergic response with a defined endpoint will be the demonstration of an increase in whealing response starting with a negative test, and progressing over the next two dilutions, increasing 2 mm in whealing size per dilution. For example, a whealing pattern for a specific antigen demonstrating an allergic response might be 5 mm for the #5 dilution, followed by 7 mm for the #4 dilution, and 9 mm for the #3 dilution. This is a positive testing sequence indicating allergy for that antigen where the endpoint is defined as the first reacting dilution in the 2 mm per dilution succession, i.e., the #4 dilution. The confirming dilution is the dilution producing the second, successive 2-mm gain in whealing size, i.e., the #3 dilution in the example. There is no reason to test past the confirming test. In fact, there is an increased risk of provoking symptoms or an adverse reaction. In an allergy battery, the endpoints for the different positively tested antigens are usually varied, thus giving results quantitated to that patient’s degree of sensitivities. Compared to traditional methods, these various endpoints then provide the basis for tailored immunotherapy, which allows starting doses of therapy to be safely more concentrated, theoretically producing improvement in symptoms within an earlier timeframe. Testing from one dilution to the next in sequence across the dilutions from weaker to stronger is called horizontal testing, which is safe but can be time consuming and labor intense. When the initial test for a specific antigen is negative (#6 dilution), it is permissible to jump two dilutions and place the #4 dilution on next. Depending upon a positive result, the third test may have to be one dilution up or down to try to confirm an endpoint. If the second test (#4 dilution) is negative, the skipping process, i.e., go to a #2 dilution, is permissible. This process, especially when the testing sequence for other allergens in the battery can be performed in this manner at the same time, is called vertical testing.

Figure 2.6 Intradermal tests on patient’s arm.

There are a number of abnormal whealing patterns which may be encountered with IDT. A discussion of these patterns is beyond the scope of the current overview, but is more extensively detailed elsewhere.^31,33

Patch Testing

As will be discussed later, there is no gold standard for the testing of inhalant allergy. However, the patch test is considered to be the gold standard for the diagnosis of allergic contact dermatitis (ACD), may be useful in the evaluation of irritant contact dermatitis (ICD), and perhaps can aid in the differentiation from other skin conditions. The history and/or the physical finding of recurrent or chronic atopic dermatitis (eczema) may be an indication for identifying contact sensitizers. The American Academy of Dermatology has set standards for the performance and interpretation of the patch test. The most commonly used product is the TRUE Test® (Allerderm Laboratories). This test has two panels of 12 standardized patch tests and evaluates 23 of the most common contact allergen sensitizers and one negative control.⁵⁵ Standardized allergens are suspended in a hydrophilic gel, attached to a waterproof, adhesive backing. For the testing of compounded standardized allergens other than the 23 offered in the TRUE Test®, Finn Chambers (Allerderm Laboratories) may be used. These 8-mm chambers are most commonly available in tape-adhered sets of 10 in two rows of 5. The back is the usual site for testing. At the time of testing, the skin should be clear of dermatitis. The panels are applied in the manner per the manufacturer’s instructions and then removed in 48 hours. Although results may be viewed 30 minutes after the tapes are removed, the suggested interpretation is made in 72 and 96 hours. Test results may be affected by the concomitant use of oral corticosteroids, the equivalent of 20 mg of prednisone per day, or the use of high potency topical corticosteroids within 7 days of application. Oral and topical H-1 antihistamines do not appear to affect the patch test. The tests are graded from 0 = no reaction (no evidence of contact allergy), +/− = mild erythema (doubtful contact allergy), 1+ = 50% of test site showing erythema with edema (possible, or false positive for contact allergy), 2+ = 50% of site showing papular erythema (probable contact allergy), to 3+ = 50% of site showing vesicles or bulla (definite contact allergy).^22,56,57 Adverse reactions to patch testing would include, but are not limited to, pruritus, erythema, burning, and hyperpigmentation. Other contact testing methods such as photopatch testing, or adjunctive tests aiding in the diagnosis or differential of ACD, such as skin biopsies, are described elsewhere.^22,56

PRIST

The PRIST is a radioimmunoassay for the quantification of total IgE. In this test a paper disc, fixed with anti-IgE, is placed in a test tube along with blood from the patient being tested. The anti-IgE is usually cultivated from an animal source. The mixture is incubated during which time available nonspecific IgE complexes with the fixed anti-IgE. The mixture is then washed leaving only the fixed IgE/anti-IgE complexes. Another solution containing radioactively labeled –IgE is then mixed in the tube, now forming the final “sandwich,” a radioactively labeled, fixed –IgE/{IgE/anti-IgE}. The label is then counted, quantitating the bound, nonspecific IgE.

Total IgE is of limited clinical value, especially when compared to specific IgE. As a predictor of the presence of allergy, total IgE level is not a reliable screen. Since the quantity of IgE is so small in the serum, a patient could be quite allergic to one or a few antigens, demonstrating elevated specific IgE levels, yet have a normal total IgE level. It is estimated that about one-half of allergic patients will have an elevated total IgE level with the usual allergic adult range being 300–600 ng/mL and the nonallergic adult 0–200 ng/mL.⁶¹ In clinical practice, norms are age-adjusted. The differential for an elevated total IgE would include allergy, parasitic infestations, atopic dermatitis, tobacco use, allergic fungal sinusitis (AFS), bronchopulmonary fungal disease, hyper-IgE syndrome (Job’s syndrome), Wiskott–Aldrich syndrome, and some malignancies. In parasite-free young children, an elevated total IgE level has been thought to predict the future emergence of allergic disease. In adults with very low total IgE levels, the chances of significant allergy is low. Changes in total IgE levels have been used to monitor therapeutic progress in both AFS and bronchopulmonary fungal disease.

Radioallergosorbent Test (RAST)

The term RAST refers to a radioimmunoassay sandwich technique in which a specific allergen is fixed to a paper disc substrate adhered to a testing well or tube. The patient’s serum is then mixed and incubated. After antigen-specific IgE in the serum has had a chance to complex with the fixed antigen (allergosorbent), the mixture is washed of excess proteins (including antigen-specific IgE not being tested), and is then mixed and incubated with radiolabeled anti-immunoglobulin E (–IgE) forming another antigen/antibody complex (paper-specific antigen/specific antigen IgE/radiolabeled{nonspecific –IgE}). After washing, the final complexes are then counted for a quantitative result (Figure 2.8). Early RAST methods used for clinical diagnosis such as the PhRAST unfortunately had insufficient levels of sensitivity. As mentioned above, Fadal and Nalebuff modified the process by lowering the diagnostic cutoff point to increase sensitivity with only a slight lowering of specificity. In addition, time of incubation was increased. This modified RAST (mRAST) was noted to correlate with IDT, with endpoint dilutions paralleling with the Fadal/Nalebuff (F/N) scoring system.^64–69 However, it is important for the clinician to realize that a quantitative in vitro test-based immunotherapy has to be validated for appropriateness and safety with an in vivo bioassay before immunotherapy is initiated. Hence the existence and function of the vial test.

Figure 2.8 In Vitro Antibody-Antigen Complexes.

RAST and other forms of quantitative in vitro tests are attractive for clinical practice. They are preferentially indicated for certain situations, some of which are noted in Box 2.9.

Caution and judgment, aided by the perspective of the allergic history, must be exercised when interpreting in vivo and in vitro results and in correlating the degree of clinical sensitivity associated with the outcomes of the allergens tested. For example, an antigen may yield a F/N score of #1 or #2 in a mRAST (F/N scores 0–6, with 6 having the highest count range) or may produce an endpoint on a #1 or #2 dilution for an IDT test. Both cases seemingly indicate a low level of sensitivity in testing. In the former situation, the test indicates low counts of IgE complexes. In the latter, endpoint reactivity is demonstrated with the application of higher strength dilutions (less reactive), as opposed to low concentrations of antigen (more reactive). These results, however, may not clearly predict the degree of symptomatology among these patients. Despite this caution, higher mRAST scores, and the higher IDT endpoints, suggest greater clinical sensitivity and symptomatic expression.

Enzyme-linked Immunosorbent Assay (ELISA)

The enzyme-linked immunosorbent assay (ELISA) uses a similar sandwich technology to the RAST and has the advantages of decreased cost for equipment and materials, and an alleviation of the need for handling radioactive materials. The test uses a polystyrene substrate and an enzyme-linked –IgE tag that produces a colormetric, fluorometric, or chemiluminescent reaction in the test mix that can be detected and quantified to assess levels of antigen-specific IgE. An F/N-like scoring system can be applied to this method. ELISA tests were designed to have better sensitivity/specificity ratios than tests such as the mRAST. ELISA methods, unfortunately, were never demonstrated to have the expected levels of sensitivity and specificity. With the emergence of the ImmunoCAP® system, ELISA techniques have reached a plateau in popularity.

ImmunoCAP

The ImmunoCAP® system (PharmaciaDiagnostics, Kalamazoo, MI) represents the newer generation of in vitro tests for specific antigen IgE. This test utilizes a fluoroenzyme immunoassay (FEIA), once again using the sandwich type technology. Specific antigen is bound to a three-dimensional hydrophilic cellulose polymer, which has the capability of binding significantly more allergen than older disk methods. This substrate theoretically allows for increased antigen binding and improved sensitivity. Patient serum is mixed with antigen-bound substrate, permitting antigen-specific patient IgE to complex. Next, the complexed substrate is mixed with an enzyme––IgE conjugate forming a secondary immune complex ({patient serum complexed-substrate}/{enzyme––IgE conjugate}). Subsequently a fluorogenic material is applied to the secondary immune complex, which results in the formation of a fluorescent secondary immune complex. Using a fluorometer, the fluorescence is read, the quantification of which correlates with the quantity of patient IgE. One scoring method for this test is known as the alternate scoring method (ASM), which reports the score for the test as a percentage of the sample measurement ratio using a 0.35 IU/mL calibration. Using this scoring method, the test correlates well with the mRAST, yet with evidence of better specificity.⁶⁰ The test also has the advantage of taking only hours to perform. As will be further noted, there is no gold standard in inhalant allergy testing. Studies have indicated however that if clinical history and/or skin testing are held as the diagnostic standard, ImmunoCAP® demonstrates very high specificity, high efficiency, and 94% sensitivity.^64,65,68,70 In addition to its use by allergy specialists, ImmunoCAP has also found growing use by primary care physicians as well as reference laboratories.

House Dust, Dust Mite, and Cockroach

These antigens are primarily perennial, indoor antigens. House dust as an entity is composed of at least 25 or more antigenic and irritant entities.^88,89 These entities include, but not exclusively, dust mite, cockroach and other insect parts, some pollen, mammalian epithelials, food particles, mold, lysine sugars from organic degeneration,⁸⁸ and residues of formaldehyde, tobacco smoke, various alcohols, and other hydrocarbons. If a seasonal flare could be attributed to these allergens, it would be whenever and for whatever length of time the weather is cold (or too hot), forcing more time spent indoors and therefore more exposure. For example, in the central Midwest, this would be approximately October through April (often noted as the reverse of baseball season). October–November is a particularly difficult inflammatory time in the central Midwest due primarily to priming and insult from the fall weed season, the beginning of the fall mold season, the start of the winter viral season, and the start of the seasonal flare of the perennial allergens.

The older the house dust is, the more antigenic it becomes mainly due to ongoing organic materials degeneration including carpets, upholsteries, bedding, air duct residue, and the list goes on. Therefore, when choosing a home, a more recently built home may be of benefit. Living in a 100-year-old farmhouse will be more antigenically challenging than a new home. Dust mites proliferate in higher humidity. Keeping the humidity between 40% and 50% is optimal. This discourages dust mite and mold proliferation and yet helps prevent mucosal drying often seen in the winter with the tendency for the humidity to drop below 35% due to the drying effect of heated air. The higher the altitude, potentially the dust mite population is lower. However, dust mite proliferation in the higher altitude dwelling may be enhanced due to the humidified, artificial environment designed for human comfort. Dust mites do not survive high temperatures. Professionally cleaning or regularly washing clothing and other cloth fabrics at a temperature >130–140°F (>50–60°C) will reduce the mite population and therefore the source of the antigenic feces. Choose hypoallergenic pillows or duvets which can be washed and tumble dried (140°F, 59°C), or easily replaced.^90,91 Mattresses can be periodically flipped over and eventually replaced. Allergy product suppliers can furnish impermeable barriers for pillows and the mattress that are becoming more comfortable. Vacuuming carpets and cloth furniture or drapes on a regular basis is indicated. Some vacuums have extra vacuum power, closed dust receptacles to prevent recirculation, shampooing capabilities, and HEPA (High Efficiency Particulate Air) filters to more efficiently remove mites and feces. Consumer reports, the internet, and allergy supply vendors are among sources for the patient to seek specific models.⁸⁹ Keep in mind that it will be impossible to fully eradicate all of the mites and all of the fecal material, yet allergic load reduction can be therapeutically relevant. Allergy supply vendors can also provide patients with carpet treatments designed to denature the fecal antigen or kill the mites, containing tannic acid or benzyl benzoate respectively. These will require periodic applications throughout the year, the frequency of which may be more dependent on how warm and humid the environment is throughout the year. Efforts to reduce “dust traps” such as excessive fabric items, shelved books and collectables, stuffed toys and animals, the presence of off-season clothing in the current closet, and plants (real or artificial) will help reduce dust exposure.^88,90

Air filtration is of help in the control of house dust as well as other indoor antigens including mammalian epithelials, mold, pollen grains, and irritants such as tobacco smoke. There are basically four levels of filtration to consider. The least expensive and the least efficient is the passive pleated or fiberglass filter found in the average, forced air heating and air conditioning systems. In addition, allergy supply vendors can provide changeable, cloth or synthetic duct grill inserts to passively filter the air as it passes the grill. Keeping beds or chairs out of the direct airflow of forced air vents will be of help. Although it may be warm and comfortable to have a patient’s bed over the warm air vent during the winter months, an increased load of dust and mold antigen may give rise to added symptoms. It may also be of help to have the ducts professionally suction-cleaned. Professional clothing and home furnishing cleaners or building contractors will quite often advertise such services. Knowing who will do this in your community will be of help to your patients. The next level of filtration is the electrostatic filter. These filters are the first level of meaningful particulate filtration capable of filtering particles measuring 0.3 mm or less. There are passive, disposable electrostatic filters which need to be replaced usually three or four times a year. There are also permanent filters which fit into the same space as the regular fiberglass filter. The permanent model needs to be washed several times a year. Letting the filter stay dirty reduces the efficiency of the filter. These are available through your heating and cooling contractor, who can also advise you about a particular filter’s efficiency rating. The next level of filtration is the electrostatic precipitator. This highly efficient precipitation occurs when air is passed over electrically charged plates, attracting charged particles to the plates. The precipitators come in portable room-sized models or may be placed directly into the heating–air conditioning system. The latter may require alteration of the existing system and has to be easily accessible since, along with the portable model, it must be cleaned periodically. If cleaning is neglected, the charged particles will bypass the plates and glom onto walls and furnishings, leaving a greasy residue. The last, and probably the most efficient filtration system is the HEPA rated filter which can be installed into a central system or may be found in a portable, room-sized model, often with a carbon pre-filter. The carbon pre-filter is attractive for irritants such as tobacco smoke. If choosing a centrally placed HEPA filter, you have to consult a heating and cooling contractor since an additional duct system may have to be installed. It is obvious that the expense involved with the different filtration options varies with the choice. The HEPA filter will select out particles 0.3 μm in diameter. The vast majority of particles in room air are 1 μm or smaller. The largest particles may be dust or pollen at 100 μm, and the smallest may be dust or smoke at 0.01 μm. The patient should be advised of the potential significance of his/her sensitivity to indoor allergens such that he/she can make a decision about the extent of filtration he/she might desire. Collectively, the options sited above should be explored, to come up with the option that makes medical and economic sense.⁸⁸

Cockroaches are controlled by professional extermination, the use of traps, over-the-counter preparations, and by making the environment less attractive to them. The American and German cockroaches are the most common types in the USA. Seeing one roach usually means there are many more. An estimated 20% of homes without visual evidence of cockroaches are cockroach infested.⁹⁰ Moist, dusty, underventilated areas with food materials readily accessible, are of high risk. Cockroaches are often brought home from the grocery store in bagged vegetables or with other semi-open packaging, making the kitchen and food storage areas high risk places. Older homes, inner-city dwellings, and high humidity (semi- and tropical climes) are some other risk factors. Following EC measures for other indoor allergens will help decrease exposure to the feces and other allergenic breakdown products of the cockroach body.⁹²

Mold

Mold spores are found both indoors and outdoors. Mold will thrive in moisture, warmth, darkness, and needs an organic substrate. Mold is a perennial allergen with flares at any time there is rain and increasing warmth. Activity increases again in the fall with the shedding of leaves and the rest of the fall decay. Indoor activity is all year around.

Areas in the home which deserve special attention include damp basements, crawl spaces, garages, bathrooms, refrigerators, leaking ceilings, underventilated closets, storage areas, feather pillows, old books, and so on. EC is directed at alleviating or controlling the sources of moisture, eradication of obvious mold, increasing ventilation, controlling excessive warmth and darkness. Dehumidifiers may be of use in the basement and the garage. Choosing to not place the patient in a bedroom over the garage or a damp crawlspace may be of help with mold, irritant, and dust exposure. Pre-packaged desiccants are available at grocery, hardware, and department stores for use in closets, bathroom cabinets, crawlspaces, and the like. Leaving a light on in high risk areas such as the basement or a closet may be of help. Monitoring humidity with a hygrometer may be necessary. Clean moldy surfaces with commercial mold/mildew cleaners or dilute bleach mixtures.⁸⁸ Increase ventilation of crawl spaces, closets, basements, or storage areas. Consulting a building contractor may be necessary to fix the leaking basement, ceiling, or garage. Plants, animal droppings, leather products, and other organic substrates are of risk. Even house dust will be a substrate for mold such as Mucor. Outdoor landscaping can have an affect on the mold-sensitive patient. A heavily landscaped, shady yard with poor ventilation due to heavy vegetation or positioning of the house relative to the prevailing breeze will increase the mold envelope of the home. The proximity of bodies of water such as a lake, pond, creek, water runoff, or the like will be of significance. Any decaying vegetation such as a compost or landscape waste will be of risk. Provoked symptoms with the exposure to freshly cut grass are suggestive of mold, more so than pollen symptoms. Mold or pollen patients working outside may have to premedicate themselves and/or wear a mask. Upon coming in from gardening or landscaping, work clothing should be taken off and left in the laundry room for cleaning and isolation of mold and pollen from the rest of the house. Mold counts tend to be increased during the cool, evening hours and anytime moist, rainy weather is followed by warm windy days. Some patients may have to alter their outside activity accordingly. Patients may also depend upon pollen and/or mold counts available to them through the local media or as a service from a local allergist.

Animal Epidermals

This group of antigens includes mammalian and avian species. The allergenic sources include saliva and urine, in addition to the epidermal structures (feathers in birds). The particles typically range between 0.1 and 1.0 μm.⁸⁸ Because cats meticulously groom themselves, dried cat saliva is a significant component of the cat-related antigens. In fact, cat is perhaps the single most important animal sensitizer. Mold in bird droppings, along with feather products, makes frequent cleaning of the bird cage a must for the sensitive patient. Eliminating a sensitizing animal will be the best solution for the seriously sensitive individual. This may not always be possible or needed depending upon the situation. Realize that it may take months of cleaning to get rid of all of the antigen products of a pet who has been taken out of the patient’s environment. This is especially true for cats. Animal isolation within the house or keeping animals outside will be of help. All allergens considered, the creation of a “safe room(s)” within the home is a must for the significantly sensitive patient. The most logical areas are the bedroom first, followed by the other room that the patient spends the most time in, usually a family or recreation room. EC efforts for all of the antigens and irritants discussed should be optimized for these rooms, especially when total home control is not going to be efficient. Washing and grooming of animals will help in most cases but may not always be easily accomplished, and in the case of washing, may not be healthy for the animal if overdone. Consulting the veterinarian will be of help on this issue and will be a source for other EC options. There are other pet options that are not mammal and avian species which may be more allergy friendly. Unfortunately, these species may or may not be desirable to the patient or rest of the family. Some patients may have to change career plans depending upon their level of sensitivity and the degree of difficulty in managing symptoms. Veterinary careers and farmhand jobs, among others, are high risk employment for some patients.

Pollen

Pollen EC can be difficult. Fully controlling exposure while outdoors is impossible. Time spent out of doors is usually the most desirable at the time of the year plants pollinate. However, knowing that daily pollination tends to be greatest in the morning hours, and that pollen counts temporarily fall after rain, may help a patient choose the time to be spent out of doors with less exposure. Windy, warm days will increase pollen and mold distribution. Removing clothing in the laundry or “dirty room” upon entering the home and/or taking a shower after a significant outdoors exposure may help prevent bringing pollen and mold spores into the indoor environment. Pollen grains will range from 10 to 100 μm⁸⁸ in diameter and, as such, will be subject to the indoors filtration options as described previously. The concentration of pollinating plants to which the patient is sensitive, found in the neighborhood and in close proximity to the home, may be important both for pollen and mold exposure. Consultation with a landscaper or the local university botanist may help avoid choosing cross-reacting plants and will give direction as to plant placement with regard to the proximity of the house when planning the landscape. Many of the other EC details noted previously will help with pollen control indoors.

Other Considerations

The issues and controversies of bacterial environmental sensitivity are discussed elsewhere and are out of the range of this chapter.⁹³ Unquestionably, bacteria may be found within the home; potentially anywhere skin/urine/respiratory/gastrointestinal soiled human or vector spreading might occur. Fomites then serve as an ongoing source for the life of the bacteria. Combinations of bioaerosols of which bacteria and, more importantly, mold are included have been implicated in the “sick building” syndrome. The term is used to describe a set of adverse health symptoms experienced within a constructed environment that lessen when the patient is out of the adverse environment. The respiratory tract and the skin are often symptomatic targets. In addition to any allergic contributions to the problem, bacterial and mold cell wall products may provide other nonspecific inflammatory effects. Molds which have been mentioned include Penicillium, Aspergillus, Stachybotrys, Fusarium, Trichothecium, Trichoderma, Myrothecium, and Cephalosporium to name a few.^92–97 Other irritant effects may be added by volatile organic compounds (VOC) such as ketones, alcohols, and formaldehydes. These factors, along with other antigenic unfriendly conditions, including building dampness, high humidity, and poor ventilation, provide an environmental situation associated with this syndrome. Suspicion of the syndrome, identification of the contributing factors, and then remediation of the building environment has been shown to improve or resolve patient symptoms. The reader is referred to lengthier discussions on this topic of ongoing investigation, elsewhere.⁹²

Pollution, both outdoor and indoor, is difficult to minimize in many cases. This source of nonantigenic triggers for inflammation may have a significant priming effect on the allergic patient and contribute heavily to the allergic load. With homes being constructed in an airtight manner, the indoor pollution may be worse than the outdoor pollution in some areas. While the EC details discussed previously will aid in the management of indoor pollution, when possible, there is no substitution for removing irritants from the immediate environment. This may include no smoking, elimination of wood-burning devices, storage of chemicals, paints, and cleaning solvents, and assurance of proper ventilation and filtration. Control of outdoor pollution may be more difficult and may not be satisfied simply by keeping doors and windows closed as practiced for pollen and mold control. The components of an areas’ pollution and comparative concentration data are available through the local EPA division. Air quality is often monitored and reported on a daily basis for numerous locales. Providing such data on a regular basis may be of help to patients. When possible, or it may be necessary, the choice of a home site or the move to a home site sufficiently away from sources of pollution may be indicated to reduce the allergic load of patients for better outcomes.

It is not uncommon for patients to announce that they will be moving, or more importantly, building a new home, and subsequently ask for advice on making the new abode more allergy friendly. A renewed and continued education of the patient on EC will be of immense help and will make some building decisions easier. A review of what, and to what degree, a patient is allergic is appropriate in this process. Contractors and other sources such as the Internet are essential in making environmentally friendly decisions. Cost is always a factor. Decisions about moisture barriers for the house, forced air versus hot water heating, a multiple storied house and basement versus one storey on a slab, the decision and choice on air filtration, landscaping design, wooden flooring versus carpeting, and the list goes on, are a few of many decisions to be made for a new home.

On occasion patients will consider moving to a new area or distant locale to improve their allergy related health. They may ask the clinician for advice. Great caution has to be taken in making this relatively rarely efficacious relocation. The patient must first realize that being allergic is a genetic predisposition and while they may experience some relief with a well-chosen move initially, the likelihood of developing new sensitivities in the new environment is high, the result of which may be disappointing to the patient and economically disastrous. Realistically, there is no locale which will be devoid of sensitizing exposures. If such a move is indicated, and with the risks of failure understood, a careful search using many sources needs to be undertaken before the move is finalized. Based on the patient’s allergic profile, such sources may include, not exclusively, pollen guides, climatic data, pollution levels, population figures, job and therefore workplace opportunities, home and building options, and so on. Such a decision made solely on EC criteria should come about with prudence and only after other management options have failed to give desired outcomes (Figure 2.9).

Figure 2.9 Algorithm for environmental control practices.

Antihistamines

Historically, antihistamines have been a mainstay, first-line choice for treating respiratory and skin allergy since their introduction in the mid 1940s. Their action is that of competitively occupying the H₁ receptor site on a potential target organ, thus preventing binding of histamine and the triggering of symptoms. Typically histamine release produces irritative symptoms of the respiratory tract, including itching and sneezing; congestive symptoms also are triggered by histamine, but other late-phase mediators may play a more critical role in nasal congestion. The newer generations of antihistamines (NgenA) have been shown to have an anti-inflammatory effect as well, thus having an action on late-phase allergic response. For example, the NgenA have been shown to reduce bronchial hyperreactivity in allergic rhinitics during allergy season.

Examples of older generation of antihistamines (OgenA) are listed in Box 2.10. Many of these agents are over-the-counter (OTC) today and some are in generic production. These agents are therefore less expensive and more readily available to the public than most prescription drugs. Diphenhydramine, for example, is still a market leader in sales. Using seasonal allergic rhinoconjunctivitis (SARC) as an example, these drugs effectively and potently treat itching, sneezing, rhinorrhea, and tearing. With their ability to cross the blood–brain barrier, sedation and potentially associated drowsiness or hampered performance is of concern, especially to the patient operating machinery, driving, or the like. This side effect may be additively enhanced if given concomitantly with other CNS depressing drugs or alcohol. Furthermore, such side effects may potentially worsen the disease effect in high risk patients such as the obstructive sleep apneic. The anticholinergic effect may make OgenAs difficult to use in asthmatics, bronchitics and sinusitic patients who need their mucoid discharge to flow easily rather than become more viscid, retentive, and obstructive. The anticholinergic effect may also promote bladder outlet obstruction in certain individuals, and is not to be used in patients with prostatic hypertrophy. Possible increased intraocular pressure is another anticholinergic effect, which precludes the use of OgenAs in patients with some types of glaucoma. Cardiac, gastrointestinal, and paradoxical stimulation side effects are also of primary concern.^98–100

Examples of the current NgenAs are listed in Box 2.11. The first of these drugs was introduced in the 1980s, with the class designed for improved side effect profiles and more favorable frequencies of dosing. The potency/efficacy performances of the NgenAs are regarded as equal, not necessarily better or worse, to the OgenAs. The incidence of tachyphylaxis seen with these NgenAs is much less than that seen with some of the OgenAs. Most of these drugs are dosed once or twice daily, resulting in improved adherence. Some of the NgenAs have a low incidence of sedation, namely fexofenadine, loratadine, desloratadine, and cetrizine, and are considered nonsedating or minimally sedating as they do not readily cross the blood–brain barrier. In fact, fexofenadine, desloratadine, and loratadine are FAA approved for pilots. However, in doses higher than the recommended respiratory dosing, desloratadine, loratadine and cetrizine have increasing incidences of sedation. On the other hand, fexofenadine has been shown to be safe at doses considerably higher than the recommended dose. Recommended doses are to be followed for fexofenadine as the increased doses have not demonstrated therapeutic benefit over the recommended, and there is a limit in the amount of the higher doses studied. Two of the earliest NgenAs, terfenadine and astemizole, were taken off the market because of the incidence of life-threatening arrhythmias associated with increased serum levels mainly due to decreased liver clearance involving the P-450 CLYP3A4 cytochrome pathway. While other NgenAs have been scrutinized for potential problems of liver clearance relating to competition for the P-450 pathway with other concomitantly taken drugs, the clinician should be familiar with the antihistamine’s package insert (PI) and the cardiologist’s ever increasing list of drugs which may affect the cardiac QT interval. One other improvement in major adverse events is the lower incidence of anticholinergic effect. The incidence for some is low enough that clinicians are using these NgenAs for patients such as select allergic asthmatics in which the drying effect of other antihistamines would be problematic.

Azelastine is currently the only topical, intranasal antihistamine FDA approved for use in the USA. Olopatadine is currently in the process of being developed for intranasal use. Azelastine has activity in both the early and late phases of allergic inflammation. Efficacy is equal or better than some of the oral NgenAs, and even more improved with the concomitant use of an intranasal corticosteroid. As with all intranasal medications, possible sensory perception side effects, e.g. aftertaste and the willingness of the patient to use a nasal spray, are issues. There is an incidence of sedation with intranasal azelastine of about 11%. Topical ophthalmic NgenAs are regarded as the most efficacious for eye symptoms, however, oral, intranasal, and parenteral medications of numerous classes of drugs have efficacy for eye symptoms. As such, these ophthalmic preparations are of value as both first-line and as add-on choices for eye symptoms.¹⁰¹ The reader is referred to other sources for a more expansive and detailed account of topical antihistamines.^98,100

Corticosteroids

For the appropriate patient, corticosteroids (steroids) have, and will, continue to play an important role in the management of atopic diseases such as eczema, asthma, and allergic rhinitis. Steroids intervene at a number of sites in both the early and late phases of the allergic reaction and inflammatory sequence. The route may be topical, oral, or parenteral. Drug-related short- and long-term adverse effects are of consideration in the management decision to choose a steroid, and limit the choice of potency, frequency, and duration of treatment. Clinician knowledge of steroid bioavailability, alternate treatment options, and risk–benefit ratios, along with a respect for the possible side effects are essential. For cases in which longer-term therapy using preparations of higher bioavailability are necessary, the clinician needs to have a plan for a routine surveillance of potential steroid-related sequellae. Such surveillance would include, but not be limited to, monitoring glucose tolerance, cataract formation, bone and joint complaints, and osteoporosis (e.g. Dexa Scanning). Recommendations for calcium/vitamin D supplements, exercise, and when appropriate, osteoporosis-limiting medications need to be appropriately made. Situations requiring long-term therapy may include some cases of asthma, recalcitrant eczema, or the nasal polyposis–sinusitis–asthma of the difficult Samter’s triad (aspirin triad) patients. The fact that idiosyncratic cases are reported of significant side effect with relatively short, average-dosed steroid courses, should only underscore the need for the clinician’s awareness of the potential risks, not to be overshadowed by the commonality of use of steroids in all aspects of medicine.

Intranasal corticosteroids are the most commonly used first line management for allergic rhinitis by otolaryngologists and allergists with primary care usage on the increase. The more commonly used molecules are listed in Box 2.12. All of these are FDA approved for seasonal and perennial allergic rhinitis, but not all are FDA approved for nonallergic rhinitis. Given the fact that the majority of patients with SAR activity have concomitant perennial and/or nonallergic rhinitis, that the anti-inflammatory action of the steroid is nonspecific, and that there is not a clear demonstration of drug-to-drug superiority, all of these molecules have been useful for allergic and nonallergic rhinitis. These molecules are currently available in a variety of carrier states, different delivery systems, with or without preservatives, with or without scent, and have evolved to compliance-friendly once- or twice-a-day dosage schedules. There are differences in bioavailability among the molecules, although significant effects of these current topical intranasal molecules on the consequences of hypothalamic–adrenal axis suppression, linear bone growth velocities, or osteoporosis are uncommon. Short-term studies have not demonstrated nonreversible HPA suppression or nonrecoverable linear bone growth suppression, although adverse 1-year effects on growth have been noted with beclometasone. By extrapolation of the HPA data, osteoporosis is not felt to be a likely issue.¹⁰² As new products of the current molecules or new molecules evolve, these concerns will need to be addressed as further studies on the current products will continue.¹⁰³ Until such studies are completed, the prevailing thought is that these products, when used as instructed in the package insert, are safe for these steroid-related side effects. However, for longer-term management, the clinician should strive to attain the lowest dosage and frequency of use to control symptoms.

Although for some patients the usage of intranasal steroids may be not feasible due to a patient’s unwillingness to use an intranasal medication, there are willing patients who are handicapped in effectively using such products due to varying degrees of mechanical nasal obstruction preventing the appropriate distribution of the drug. In the case of severe swelling, intranasal steroid treatment may need to be augmented with the use of short-term oral or topical decongestants, or an initial systemic/oral steroid to allow the intranasal steroid better access and time to successfully take over the management. There are times when adynamic or fixed mechanical obstructions such as a deviated nasal septum, concha bullosa, or intranasal synechia are not affected by decongestion and need to be surgically altered for better medication efficacy and general airway improvement. The practice of injecting intranasal steroid is mainly limited to treating hyperplastic membrane disease of the turbinate. This modality, which carries a risk of adverse effects including blindness, is described elsewhere. The more common side effects of intranasal steroids include nasal stinging and sore throat, headache, and epistaxis, with nasal septal excoriation/perforation and nasal or oral candidiasis being possible but less common. Proper patient instructions on application of the drug are designed to maximize intranasal distribution while keeping nasal septal stimulation and possible bleeding to a minimum.

At present, while more serious steroid sequelae are not felt to be of significant concern with the intranasal route, such is not the case with inhaled, injected, topical, or oral steroid therapy. Once the drug enters the body, the bioavailability of the drug and the potential for longer-term sequelae is determined by the absorption/storage/excretion characteristics and potency of the molecule, the dosage and frequency of the administration, and efficiency of liver clearance. Of particular note to the otherwise informed clinician is the possibility of steroid-related adverse effects with higher potency skin topicals over larger skin areas depending on length of time of therapy. Orally inhaled steroids have a greater bioavailability than intranasally applied molecules and carry a higher potential for side effects. Some patients, labeled as “steroid responders,” are particularly sensitive to ophthalmic steroids and respond more easily with increased intraocular pressure and the possibility of accelerated glaucoma and/or cataract formation. It is the clinician’s responsibility to be knowledgeable on the use and the potential risks of steroid therapy.

Leukotriene-modifying Drugs

In the USA, the leukotriene-receptor antagonist montelukast is available for use in the treatment of SAR, PAR, and asthma. Other leukotriene-receptor antagonists are also available for the treatment of asthma, including zafirlukast and pranlukast. Another drug with leukotriene-inhibitory effects, zileuton, is also available for the treatment of asthma, and works through the inhibition of the 5-OH-lipoxygenase enzymes in the conversion of arachadonic acid to the cysteinyl leukotrienes. The cysteinyl leukotrienes are proinflammatory products of the arachidonic acid metabolic cascade and affect allergic inflammation independent of histamine effect. Montelukast may be used as a first-line choice for treating SAR and PAR, as well as in the treatment of asthma. Nasal, eye, and total symptom scores are improved. The drug may also be useful as an add-on drug when other drugs such as an antihistamine and/or intranasal steroid have not given a desired control of symptoms. The belief in a decongestion potential for this drug makes it attractive for situations where some degree of decongestion is desirable but in which the use of a sympathomimetic drug is avoided due to the risk of side effects. Headache and sometimes insomnia are common, yet infrequent, side effects. The use of montelukast for migraine (another disorder with inflammatory potential) is also currently under evaluation. The reader is referred to other sources for further in-depth information on montelukast and the other molecules.^104,105

Decongestants

Decongestants are α-adrenergic agonists which are sympathomimetic in nature and decrease vascular congestion in the nose, allowing less respiratory tract obstruction. These drugs may be used orally or as topical intranasal agents. The oral preparations may be used alone or in combination with other medications such as antihistamines or mucolytic agents. Of most concern with decongestants are their potential side effects. Cardiovascular side effects such as blood pressure elevation, and cardiac rate and/or rhythm modulation warrant clinician discretion in patient selection and length of time for therapy. In patients selected for such treatment, blood pressure should be monitored and patients warned to report any incidence of headache or palpitations. Anxiety, insomnia, headache, and bladder outlet obstruction are some of the more common complaints noted. While the CNS stimulatory effect may appear to negate the sedation effect of an older generation antihistamine, the use of a decongestant will not reverse effects on performance impairment caused by the OgenA.

Topical intranasal preparations have the best efficacy of all medications for decongestion; however they also carry, with prolonged use, the significant risk of a rebound phenomenon that actually promotes congestion and dependence, called rhinitis medicamentosa. This tachyphylaxis and dependency may be lessened by short-term use of just a few days. This potential problem may be best treated by cessation of the drug alone or in combination with other symptomatic medications, most notably intranasal or short-term oral/systemic steroids. A number of days of decongestant cessation are usually required to reverse the rebound effect and gain better symptom control. An alternate modality used to treat rhinitis medicamentosa is the use of an adjunctive weaning protocol such as applying successively weaker concentrations of the intranasal decongestant by progressively refilling a half-used bottle of spray with saline until the patient is using only a buffered saline nasal spray devoid of the decongestant.

Pseudoephedrine has been the most commonly used molecule for oral preparations. Phenylpropanolamine and phenylephrine have also been used orally. Phenylpropanolamine preparations have been withdrawn from the market due to an incidence of intracranial hemorrhagic stroke mainly in females. Many of the decongestant drugs are available OTC. The availability and allowed quantity for purchase of pseudoephedrine is now monitored by the pharmacist in the USA, since it can be used as a substrate in the illegal production of methamphetamine. This problem has led to the reformulation of many decongestant preparations using other decongestants, with the use of phenylephrine orally increasing in popularity.

Decongestion may additionally be enhanced by exercise, weight loss, avoidance of other concomitantly taken drugs for the side effect of nasal congestion, removing fixed intranasal obstructers, and reducing allergic load. The use of decongestants in the right patient may complement or facilitate the actions of other symptomatic drugs. As with the use of steroids in the treatment of allergic disease, the clinician needs to be aware of the risks involved with using this class of drug.

Mast Cell Stabilizers

Mast cell stabilizers prevent the release of mast cell mediators such as histamine through stabilization of the mast cell membrane. These agents are most effective when used prior to antigen exposure. Sodium cromoglycate (cromolyn sodium) has now been available in an intranasal format OTC for almost 10 years. As such it is available as a first-line drug for management of mild allergic reactions and as an add-on choice to complement other regimens. The drug is relatively free of side effects, but has to be used for effect four times a day. Nedocromil is much more potent than cromolyn sodium but is only FDA approved in the USA as an inhaled preparation for asthma, and as a topical ophthalmic. Other ophthalmic mast cell stabilizers include cromolyn sodium, ketotifen, and pemirolast, and topical antihistamines such as olopatadine also demonstrate mast-cell stabilizing effects. Cromolyn sodium is also used as an oral preparation for the treatment of mastocytosis and has been used off-label in the management of food allergy. Other drugs of this class, such as lodoxamide, continue to be studied and/or await FDA approval.

Anticholinergic Drugs

These drugs are available in oral and intranasal preparations. The side effect profile of the oral route is quite significant, which has limited use by this route and the number of preparations available. Ipratropium bromide is available in two intranasal formulations (0.03% and 0.06%) for the management of thin rhinorrhea. Along with intranasal azelastine and fluticasone, these preparations are FDA approved for management of vasomotor (idiopathic) rhinitis. Examples would be “skier’s nose” and gustatory rhinitis. Intranasal ipratropium bromide may be used one to three times a day with a relatively small side effect profile. These preparations may be a good synergistic choice as an add-on medication in difficult cases for allergic and nonallergic rhinorrhea control. An OTC preparation of a less potent formulation is available.

Mucolytic Agents and Mucus Management

Adequate mucus toilet is an important adjunct in the management of virtually all of the inflammatory conditions of the respiratory tract. It is neither healthy nor readily possible to eliminate mucus production. Mucus problems center around excessive mucus production, poor quality of mucus produced, bacterial/fungal colonization, and/or impaired mucus transport. Adequate, or if possible increased hydration with water is the foundation of mucolysis, quality mucus production, and transport. Often, improvement with this alone is enough to give desired improvement. Alcohol, coffee and some teas (caffeinated or not), milk, and other commonly available drinks may not help or even detract from mucus management goals. Humidity control, as commented on previously, is important to mucosal moisture, tissue turgor, mucus quality, and transport. Other medications the patient is taking that are essential to managing the patient’s other medical illnesses can create or add to problems with mucus physiology. Lavage or irrigation of the mucosal tract when possible may be of help. For example lavage may include the use of buffered physiologic saline ophthalmic drops to help treat “dry eye” syndrome or evacuate thick and/or increased conjunctival mucus. In addition to buffered saline spray or gel preparations there are a number of sinonasal wash or irrigation formulations to be considered for increasing moisture, transporting mucus and washing out microbials, irritants, and/or antigens. In some instances the amount of refractory intranasal tissue edema may be improved by the use of a hypertonic solution which will help transport free water across the mucosal border.

While water is the best mucolytic, guaifenesin is the most common drug on the market used for this purpose. For the adult, the dosage ranges up to 1200 mg bid of the long-acting preparations. There are preparations which are combined with other agents. There are also preparations for children. Most of the guaifenisin preparations are available over the counter. Side effects most commonly reported include GI symptoms such as nausea, and the sensation of dryness, especially if the patient does not drink enough water. Patients need to be told that adequate or increased water intake is needed for guaifenesin therapy to be successful. It is not clear as to whether guaifenesin actually lyses mucus or stimulates the production of a thinner, better quality mucus through a vagally mediated mechanism. Likewise, oropharyngeal rinsing and/or nebulized saline may be of benefit for the epilaryngeal and/or tracheobronchial tracts. Mucus condition and the adequacy of its transport are considerations for the clinician.

Monoclonal Antibodies and Other Immunomodulators

Omalizumab (Xolair®, Genentech) is the sole anti-IgE drug approved for human use, and only for severe asthma in adults. It is a recombinant humanized IgG1 monoclonal anti-IgE antibody that binds to nonspecific unbound IgE. Because of its structural/functional composition, it should not provoke anaphylaxis, although there have been a few reported cases.¹⁰⁶ Patients have to satisfy certain elements in their asthmatic profile, have at least one positive skin test (usually to a perennial allergen), and demonstrate an elevated total IgE level. The dose, given subcutaneously monthly or twice a month in divided doses, is formulated on the basis of patient weight and the initial total IgE level. Although dramatically decreased levels in free IgE are seen after the initiation of omalizumab, clinical response may take a number of weeks. Omalizumab has an effect on both early- and late-phase response, a decrease in tissue, airway, and peripheral eosinophilia, and is associated with up to a 50% reduction in asthmatic exacerbations.^2,107 The changes in eosinophilia are seen in the entire respiratory tract and skin as well.^108,109 Interestingly changes in bronchial hyperreactivity to challenge with methachloline and to airflow obstruction are not as dramatic.¹¹⁰ Strunk and Bloomberg² comment that the place for omalizumab in the armamentarium of management has not been fully defined, however they feel there are patients who may most likely benefit from such therapy. These patients would include perennial allergic asthmatics on high doses of inhaled steroids (at higher risk for side effects), unstable asthmatics with frequent flares of asthma, and those patients with severe disease and poor medication adherence. Although omalizumab is not approved for the treatment of allergic rhinitis, it has shown success in decreasing symptoms of rhinitis.^111–115 Currently, management with omalizumab is expensive, and there have not as of yet been any well defined endpoints of therapy. In addition, the long-term side effect profiles, including the risk of neoplasm and parasitic disease, have not been clarified. As with any other form of therapy, the risks and benefits will have to be further evaluated.

Monoclonal antibody preparations for activity against the proinflammatory cytokine interleukin 5 have been under development by at least two companies. An in-depth description of their use is beyond the scope of this chapter.

Summary

It is apparent that there are a number of pharmacologic agents available to the clinician in the management of allergic disease. Such management will be presented in more detail in the appropriate problem-related chapters. The armamentarium will continue to grow as newer agents are developed. Choice of treatment method depends upon the medical profile, economic factors, availability, and the likelihood of patient adherence. Figure 2.10 demonstrates an algorithm to help the clinician through a general management process. It is clear that there are situations when environmental control of the allergic load (EC) and pharmacologic symptomatic medication (Rx) are not enough for the desired outcome and quality of life. In such situations, specific immunotherapy is indicated.

Figure 2.10 Algorithm for allergy decision making.

Benefits and Indications – the “Why,” “When,” and “Who” of IT

When possible, the elimination of allergens from the sensitized patient’s environment remains the treatment of choice for the allergic patient. However, most patients are allergic to several antigens, and antigen avoidance can be difficult and impractical. As such, environmental control (EC) of allergens and irritants is still the foundation of management. While avoidance may be sufficient to achieve desired outcomes in some patients, symptomatic medication (Rx) will be needed in the majority of allergy patients. The most common indication for instituting IT is the lack of effective treatment outcomes and quality of life improvement using EC and/or Rx. In addition, there are patients who wish to be aggressive at the outset, choosing IT along with EC and as-needed Rx in the initiation of management. It has been estimated that 15–20% of patients skin-tested choose IT as part of their initial management. Risk, benefit, compliance, and economic factors are always considered in this case-by-case decision process.

A major consideration is management and reduction of the patient’s allergic load. EC involves reducing the allergic load presented to the allergic patient. The anti-inflammatory and anti-proinflammatory effects of Rx also reduce allergic load in the broader sense. In reality, the desensitization effect of IT also reduces the allergic load by making patients less sensitive to allergens and more tolerant of exposures. As such, IT also decreases the adverse effect of priming. Arguments can be made for using IT to lessen the likelihood of the patient developing further sensitivities by downregulating specific, and subsequently, global sensitivity and priming. It is further argued, IT may prevent the emergence of atopic involvement of other target organs, such as preventing or delaying the emergence of asthma in the estimated 30% of allergic rhinitics who are at risk of developing hyperreactive lower respiratory tract disease.

The potential benefits of IT are many. First, maximal therapeutic outcomes may be attainable with the addition of IT. For some complex or difficult patients, the addition of IT may produce the best possible outcomes. Furthermore, specific antigen IT is the only proactive treatment that can lessen the patient’s sensitivity to specific antigens. The ultimate goal of allergy treatment would be the hope for a “clinical cure,” i.e., attaining an allergic state desensitized sufficiently to require little or no medication at all. Long-term effects of using anti-IgE with IT are not established at this writing, but may potentially yield an efficacious method for IgE immunomodulation and the possible “clinical cure” in select patients. The potential reduction in medication requirements is an attractive goal for many patients. Such a reduction can be economically beneficial, lessens the chances of medication nonadherence, reduces the incidence of drug-related side effects, and further improves quality of life by changing the regimented discipline of the drug schedule. Case-by-case the cost and regimen of IT has to be weighed with Rx. For someone who is comfortable with their established degree of EC and Rx without adverse effects or financial burden, there may be no real reason to consider IT. For many patients, the cost and time spent in a course of 3 to 5 years of IT is more attractive and cost-effective than the global cost of management of the allergic problem and its secondary sequelae, such as recurrent morbid infections, time lost from work/school, or poor performance. This economic benefit is highly dependent on the patient adhering with the IT program and the physician attaining high enough levels of delivered antigen over the appropriate time frame to effect desensitization.

It is an absolute contraindication to institute IT in a patient without proven and clinically relevant IgE-mediated disease. If not absolute, it is arguably a relative contraindication to perform in vivo testing or IT in patients on beta-blocking agents. Should an adverse reaction to testing or IT occur requiring epinephrine in the rescue, a possible unchecked alpha adrenergic effect of the epinephrine could lead to disastrous sequelae such as severe hypertension. Such reactions have been reported even with beta-blocking topical ophthalmics used in treating conditions like glaucoma. In addition, many clinicians regard beta-blocking agents as “pro-allergic,” often advising patients to seek other alternative medications when possible. The estimated impact of the beta-blocker on the allergic problem has to be weighed against the impact of its discontinuance on the medical problem for which it was prescribed. ACE inhibitors or ACE blockers concomitantly used in patients on IT can also be an area of concern to allergists. These two drugs (the inhibitors more so than the blockers) have been associated with an incidence of angioedema of the upper airway, at times causing potentially life-threatening airway obstruction. The mechanism is thought to be non-IgE-mediated, involving kinin metabolism. However, the incidence of angioedema appears to be increased in patients with IgE-mediated problems. The question as to whether treating patients with IT who are also concomitantly on an ACE-inhibitor or ACE-blocker will further predispose them to the risk of drug-related angioedema has not been fully answered as of this writing, although in clinical practice adverse events would appear rare. A corollary concern is whether patients with IgE-mediated disease should be on an ACE-inhibitor or ACE-blocker at all. These drugs have significant clinical value for serious medical problems quite often of great importance to the well being of the patient. The clinician(s) have to make decisions based on the risks and benefits involved.

Using IT in pregnancy is another area needing special attention. For the allergic patient who becomes pregnant, her overall degree of potential reactivity can become somewhat unpredictable. It is currently recommended that pregnant women should not be in vivo tested, nor should they be started on IT. Women who are already on IT and become pregnant may continue IT as long as it has been well tolerated before. In this situation there should be no escalation of dosage (dose remains the same), the patient has to be monitored closely, the allergist has to certify the benefit of maintaining the therapy, and the continuance of IT has to have the approval of the patient, her obstetrician, and any other relevant clinician. An adverse reaction due to IT in a pregnant woman may be morbid or life threatening to the patient and/or the fetus.

HIV-infected patients have generally not been considered candidates for IT as there is concern over unpredictable immunomodulation, which might have adverse effects on their already immunocompromised state. One current clinical problem is that HIV-infected patients are now living for increasingly longer life spans without developing active AIDS. This fact will lead to a re-evaluation of how physicians will approach the many more common medical problems of longevity in these patients, including how their HIV maintenance drugs affect the patient long term and how they interface with other medical problems and their management. The use of IT is also not recommended for patients with multiple sclerosis due to the unpredictability of promoting acute exacerbations of the MS. Similar arguments have been made for patients with cancer, collagen vascular diseases, and other select autoimmune conditions. This clinical picture is further complicated by the more common use of immunomodulating and immunosuppressing drugs for an ever growing number of medical problems. Lastly, the consideration of the institution of IT should be taken with the utmost caution in any patient who would predictably have a potentially serious or catastrophic outcome with the occurrence or the management of an adverse event from the therapy. In this last setting, generally the risk outweighs the potential benefit.

There are age considerations in deciding who is a candidate for IT. As expected, these considerations pertain to the age extremes, the young and the elderly allergy patients. It is unusual for patients up to 2 or 3 years of age to be significantly allergic to inhalants. Typically the early expressions of sensitivity with any clinical significance begin with foods, then perennials, followed by seasonal inhalant allergens. Clinically relevant IgE-mediated inhalant sensitivity needs to be documented before injection IT is contemplated. Children from age 2 or 3 up to puberty are in the earliest range of consideration. The best approach, in general, is conservative, i.e. considering IT only when good effort of control of symptoms and quality of life improvement utilizing EC and Rx have failed in some compelling way. In such patients, however, remember while IT may improve outcomes and reduce sensitivity and allergic load for the present, it may subdue but not prevent the patient from forming sensitivity to other allergens as time and new exposures dictate. Just as some studies have indicated that empiric treatment of the atopic child with EC and Rx may have a delaying impact on the emergence of allergic conditions such as asthma, it may not be preventative. There are no long-term follow up studies to support the efficacy of early-age IT being preventative in the long term for the further evolution of allergic disease. IT in this age group should therefore be utilized for current symptomatic improvement, with the hope of curbing symptoms or other allergic disease emergence in the future. Quite often patients may experience a spontaneous short- or long-term improvement in symptoms during puberty through the teen or early adult years, with some patients experiencing even lifetime change in symptoms. This “growing out of allergy” period may end sometime in the late teen years, or early to late adulthood with a recrudescence of symptoms of varying degrees. Suspicion, testing, and the treatment of allergy in the senior population was thought to be foolish, considering the incidence of sensitivity generally decreases with age. While the development of new-onset allergic disease in the elderly is very uncommon, even the senescent immune system is capable of mounting IgE-mediated disease, and these patients may benefit from IT in the right setting. This observation is further supported by the fact that patients are living longer, healthier, and more active lives demanding a higher level quality of life with prevention or delay of the sequelae of chronic active allergic inflammation.

The mechanics of formulating, initiating, maintaining, trouble shooting, and discontinuing IT are not in the scope of this chapter and are well referenced elsewhere. There are widely accepted regimens for subcutaneous injection IT whether the formulating data is derived from epicutaneous prick/puncture (with/without fixed intradermal) skin testing, intradermal dilutional testing (IDT), modified quantitative testing (MQT), or in vitro tests such as the mRAST or ImmunoCAP. The use of sublingual IT, not yet widely studied or used in the USA, is also well referenced.¹¹⁷