Skin testing for inhalant allergy 2003: current strategies

SUPPLEMENT TO

Otolaryngology– Head and Neck Surgery OCTOBER 2003

VOLUME 129

NUMBER 4

Skin testing for inhalant allergy 2003: Current strategies JOHN H. KROUSE,

MD, PhD,

and RICHARD L. MABRY,

MD,

Detroit, Michigan, and Dallas, Galveston, and San Antonio, Texas

S kin

testing has been in common use for the diagnosis of inhalant allergy since the 19th century. With the identification of pollen sensitivity as the causative factor for fall hay fever in 1872,1 physicians could begin to approach specific methods to diagnose and treat this common condition. Within 1 year, Blackley2 performed the first skin tests with pollen extracts, noting that a wheal would quickly develop at the site of pollen placement on excoriated skin in sensitized individuals. From these early experiences with cutaneous testing for inhalant allergy, many methods and systems have been developed over the past 130 years to provide an accurate diagnosis of inhalant allergy among symptomatic patients. For many years, the primary approach that has been practiced by the majority of otolaryngic allergists and taught by the American Academy of Otolaryngic Allergy (AAOA) has been skin endpoint titration (SET)—a quantitative method for the diagnosis of inhalant allergy. SET has been demonstrated to be an extremely safe method of skin testing,3 allowing immunotherapy to be administered both in the office and at home with From the Department of Otolaryngology, Wayne State University (Dr Krouse), and Department of Otolaryngology, University of Texas Southwestern Medical Center, Department of Otolaryngology, University of Texas Medical Branch, and Department of Otolaryngology, University of Texas Health Science Center (Dr Mabry). Reprint requests: John H. Krouse, MD, PhD, 540 E Canfield, 5E-UHC, Detroit, MI 48201, USA; email, jkrouse@med. wayne.edu. Copyright © 2003 by the American Academy of Otolaryngology–Head and Neck Surgery Foundation, Inc. 0194-5998/2003/$30.00 ⫹ 0 doi:10.1016/S0194-5998(03)01398-6

adverse reactions occurring only rarely. In SET, various dilutions of antigenic concentrates are applied in a sequential manner to not only demonstrate the presence of allergy but to quantitate the degree of sensitivity and determine the safe initial starting dose for desensitization immunotherapy. The broadly accepted approach to SET embraced by the majority of otolaryngic allergists was formalized by Rinkel,4 who observed that 1:5 dilutions of antigen applied in sequentially increasing concentrations provided reliable and clinically useful information in guiding successful immunotherapy. Over the past decade, a number of forces have led otolaryngic allergists to alter their approach to practice. Broadly, these complementary forces can be described as scientific and socioeconomic. The profession of medicine and the provision of medical care are becoming increasingly directed by evidence-based practice, the reliance on objective data from prospective clinical research to justify the use of a specific procedure or treatment. With the influence of governmental oversight and thirdparty payers, physicians must demonstrate that the techniques they use to approach a clinical problem are both safe and effective. Examination of scientific factors in the testing and treatment of patients for inhalant allergy demonstrates that although SET continues to be a useful technique for otolaryngic allergists in diagnosing and treating inhalant allergy, there is little controlled research documenting its effectiveness. Although scientific support has been demonstrated in at least three articles,5-7 there remains only limited experimental evidence supporting the efficacy of SET-based immunotherapy. Despite S33

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these limited controlled data, clinical experience and expert evaluation have shown SET to be useful and effective in the diagnosis and treatment of inhalant allergy. Position statements from both the Allergy Panel of the American Medical Association (AMA) Council of Scientific Affairs8 and the American Academy of Allergy, Asthma, and Immunology9 describe intradermal dilutional testing such as conducted with SET as effective for quantifying patient sensitivity to inhalant allergens. For this reason, techniques of dilutional testing continue to be used in practice with clinician confidence. Another area where more scientific investigation has recently been called for involves the sensitivity and specificity of intradermal testing as compared with prick tests. Several recent studies have suggested that intradermal testing with high concentrations of antigen (1:500 to 1:1,000 weight per volume [wt/vol]) may lead to false-positive findings and, therefore, to unnecessary and unwarranted immunotherapy.10-12 In one recent study, Gungor et al13 demonstrated that SET was a poorer predictor of response to nasal challenge than was skin prick testing. They believed that prick testing was both more sensitive and more specific than SET. Clinical experience challenges these observations, and there is a need for further research to clarify and define the significance of testing with high antigen concentrations. The clinical importance of positive SET results in this circumstance has been debated for years.14 The second set of forces that impact on otolaryngic allergy practice are socioeconomic factors. Despite the accepted utility of SET in guiding immunotherapy, it is more time-consuming and labor-intensive than some other forms of skin testing.14 There are more supplies involved in the form of syringes, vials, and expended antigen. A recent study by Shah and Emanuel15 demonstrated that the cost of performing a complete SET battery is approximately 3 times greater than the cost of prick testing for the same number of antigens. In the modern world of cost-effectiveness, the balance between information obtained and funds expended has now become a consideration. Adding to the dilemma of the physician who depends on SET as a preferred test method, some insurers fail to reimburse for SET, classifying it as

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an unproven or experimental technique. In addition, there have been policy statements issued by various carriers limiting the number of antigens and/or tests that can be conducted on a specific patient, as well as limiting the frequency with which patients can be retested. These limits often center around 60 to 65 specific intradermal tests, whether used in single-dilution testing or sequentially, as in SET. Finally, reimbursements for virtually all medical services have decreased over the last decade, resulting in lesser revenues to physicians for services provided and making it difficult for physicians to provide services for which they cannot expect payment. The combined impact of these factors is that the variable and fixed costs for SET are higher when compared with other forms of testing, whereas reimbursements for services performed continue to decline. These resultant restrictions for skin testing have had a significant impact on the ability of otolaryngic allergists to maintain cost-effective and viable allergy programs. Because of these two complementary forces, otolaryngic allergists have of necessity examined methods of increasing the efficiency and decreasing the cost of allergy testing while maintaining safety and efficacy for their patients. The first step has been to incorporate screening methods into their testing protocols. Another step has been to use a blending of prick and intradermal techniques. The AAOA, in response to both scientific and socioeconomic factors, has recently adopted principles addressing the use of screening tests, including the number of tests to be routinely used for the diagnosis of inhalant allergy in most cases. Methods of blending various types of skin testing have been developed, refined, and taught over the past decade, and the modern otolaryngic allergist should be conversant with all of the testing tools now available, to render good patient care in a cost-efficient manner. This monograph is offered to provide a concise and practical description of the theory and practice of these techniques. SKIN TESTING STRATEGIES FOR INHALANT ALLERGY In January 2003 the Board of Directors of the AAOA endorsed strategies in testing for inhalant allergy. To correspond with the terminology

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change introduced with the 2003 AMA manual Current Procedural Terminology 2003 (CPT Manual),16 for procedure No. 95027, the term SET will reflect only one specific approach to dilutional testing. The broader practice of sequential intradermal testing will now be known as intradermal dilutional testing (IDT). For future AAOA communications and in AAOA courses and sponsored research, the term SET will be replaced by IDT. This does not mean an abandonment of the concept of SET, but rather an extension of the concept of quantitative or dilutional testing. As noted in the recommendations, “SET is one early form of IDT.” The 2003 AAOA guidelines suggest 4 principles in testing for inhalant allergy: 1. The goal [of allergy testing] is to identify antigens to which patients are symptomatically reactive and to quantify the sensitivity if immunotherapy is contemplated. 2. There are a variety of acceptable techniques. For inhalants, the following are acceptable techniques: A. Prick testing B. Intradermal testing C. IDT D. In vitro testing 3. Allergy care shall be directed by a trained and competent physician who regularly participates in the care. 4. Members shall practice in ethical and fiscally responsible ways. A. Screening: Screen with no more than 14 relevant antigens plus appropriate controls. B. Antigen survey: If screening is positive and immunotherapy is contemplated, use no more than 40 antigens. More extensive testing may be justified in special circumstances. C. Quantification for safe starting point: Use no more than 80 IDT tests routinely. More extensive testing may be justified in special circumstances. Otolaryngic allergists choosing to follow these strategies will have several options for testing their patients with inhalant allergy. Although this monograph does not attempt to be a definitive compendium of all specific skin testing methods

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with all of their nuances, it will present information and strategies that will be useful in treating patients with inhalant disease. Furthermore, a future uniformity in approach and terminology should facilitate evidence-based research into these testing modalities and enhance communication of findings among physicians (and to thirdparty payers). SCREENING All testing for inhalant allergy should begin with an allergy screen. Screening techniques have proved to provide a rapid, efficient, and costeffective method to assess the presence or absence of allergy in the clinical setting. The principle underlying all screening techniques is based on the observation that patients with allergic sensitivities will likely react to one of several common antigens tested through either in vivo or in vitro methods. The absence of reaction to these common antigens suggests that the likelihood of the patient having allergic sensitivity to a broader panel of antigens is low. Screening techniques therefore use a small but representative number of allergens commonly found in the practitioner’s geographic region. Screening panels can be as narrow as 6 to 8 antigens.17 Panels with 12 to 14 antigens, however, have been shows to have better sensitivity in the detection of inhalant allergy, and their use is consistent with the 2003 AAOA recommendations.18,19 Several principles are essential in the use of screening methods for inhalant allergy. The screening battery must represent relevant classes of antigens, both seasonal and perennial, to which patients are commonly exposed. Pollens from each of the three major seasonal allergens (ie, grasses, weeds, and trees) are used to represent seasonal antigens. Pollens included in the panel should be representative of common antigenic substances in the relevant geographic region. Perennial antigens include mold, dust mite, animal dander, and (in certain circumstances) cockroach. Because molds demonstrate poor crossreactivity, several genera should be included in the panel. Allergy to dust mites is common, so at least one species of dust mite should be included in the screening panel. Because cross-reactivity to both common dust mites is not perfect, consideration

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Table 1. Typical screening battery Timothy grass Bermuda grass Short ragweed White oak Eastern cottonwood Alternaria Helminthosporium Penicillium Dermatophygoides pteronyssinus Dermatophygoides farinae American cockroach Cat

may be given to testing for both Dermatophygoides pteronyssinus and D farinae. Cockroach may appropriately be included in a screen in the presence of asthma or in patients living in older dwellings. Cat antigen should be included, not only because of the ubiquitous nature of cat dander, but the tendency of cat owners to deny exposure, for fear of being asked to eliminate their pets. Additional testing is not generally indicated if the allergy screen is negative. When one specific test in the allergy screen is positive, other members of that antigen group should be tested to further characterize the nature and degree of the sensitivity, taking into account the cross-reactivity noted among various families of antigens. Further testing is especially important with molds, as patients with one positive mold result are often sensitive to several additional molds. Testing within families is also necessary for planning immunotherapy, because it allows quantification of the degree of allergy for each specific antigen. An understanding of the principles of cross-reactivity among antigen families is essential to avoid testing and treating for antigens that are strongly cross-reactive. Because grass pollens are often cross-reactive, appropriate testing is important to avoid precipitating anaphylaxis. Screening may be performed successfully with either in vivo or in vitro methods. A typical screening battery is shown in Table 1. Refinements should be made as necessary for use by otolaryngic allergists based on patterns of allergens in their individual practices. For the purposes of this monograph on skin testing, only in vivo methods of screening for inhalant allergy will be discussed here. The practitioner should realize that

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in vitro methods are acceptable and can be used with effectiveness that is similar to the techniques discussed herein. One simple and cost-effective method of screening involves the use of a prick test battery of 12 to 14 antigens with appropriate positive and negative control tests. This battery may be followed by single dilutional intradermal tests for selected antigens that are negative on prick testing but for which significant clinical suspicion exists. Single dilutional intradermal testing is not recommended without a preceding negative prick test, as there can be an unacceptably high rate of significant adverse local and systemic reactions with this approach. In another approach, dilutional intradermal techniques can be used to screen the 12 to 14 relevant antigens and their appropriate controls. Many otolaryngologists have traditionally relied on dilutional testing techniques for diagnosis of inhalant allergy and are more familiar with using this method for their entire testing battery. Screening with IDT begins by testing at an appropriately safe dilution with a low concentration of antigen. The added benefit of testing with IDT is also the detection of sensitivity to common representative antigens. If the IDT panel is negative, no further testing would be warranted. In the case of positive screens with a prickbased technique (with or without single dilution intradermal testing), if immunotherapy is to be administered, additional testing is necessary to further characterize the range of allergic sensitivities as well as to quantitatively estimate the degree of those sensitivities. In practice, positive screening tests are used to represent antigen families, and other common antigens within those families that are present within the geographic region of concern are then tested. For example, if a patient tests positive to a screen for short ragweed antigen, additional clinically important weeds for that region would then be tested. The testing method used to follow-up on positive tests obtained at screening should assess a representative sample of important, relevant antigen families, as well as providing necessary information regarding the patient’s degree of sensitivity. This quantitative information will be applied in the development of treatment vials used for immuno-

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therapy. Quantitation can be estimated with various methods, to be discussed below. SKIN TESTING TECHNIQUES IDT SET: The basis for IDT. In 1952 Dr Herbert Rinkel, a Kansas City internist/allergist, began the custom of presenting postgraduate courses in allergy that highlighted the technique he had been using for over a decade. This material formed the basis for much of the early teaching of the skin test method that he termed serial dilution testing.20 The unique contribution of Dr Rinkel was an emphasis on quantitative testing to determine not only the presence or absence of cutaneous reactivity to allergens but the degree of that reactivity. From this, he believed that a safe and effective starting dose for immunotherapy could be determined for each specific antigen. Rinkel’s modification of the earlier work of Dr French Hansel21 used 5-fold antigen dilutions, rather than the 10fold dilutions used by Hansel and by many current allergists. Rinkel4 found that by using 1:5 dilutions, a constant increment in whealing response was obtained in over 70% of patients and that the smaller change between dilutions avoided overdosing. The methods of skin testing favored by otolaryngic allergists and the manner in which the results obtained are used to administer immunotherapy have continued to evolve. Nevertheless, an understanding of the principles of the seminal form of IDT, known as skin endpoint titration (SET), is invaluable to today’s practitioners, whatever method of testing they use. Familiarity with the normal and abnormal whealing responses encountered during intradermal testing, as well as the relationship of SET to other testing modalities (eg, prick, in vitro), will allow the skilled physician to move with facility between these methods and integrate them into his or her practice.22 This section will provide a discussion of the theory and practice of classic SET. Normal and abnormal whealing responses of the skin. The intradermal injection

of 0.01 mL of diluent, or any nonreactive liquid, will produce a skin wheal of approximately 4 mm diameter, which enlarges to a 5-mm-diameter through physical spreading.23 In the case of IgE-

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mediated allergy, mast cells in the skin, with specific IgE for the antigen tested fixed to their surface membranes, react with the antigen that is injected. After a delay of up to 5 minutes, the skin begins to swell as a result of increased vascular permeability and transudation of plasma proteins into the tissues, with a corresponding influx of water. This swelling, which produces the “wheal” response, is proportionate to the amount of mast cell activation and is therefore a specific indicator of IgE-mediated release of histamine and other mediators. The various mediators released include substance P and platelet-activating factor, which cause a local erythema, termed the flare reaction. Mediators also trigger sensory nerves in the skin, causing itching. When 0.01 mL of an allergen to which a patient is allergic is placed intradermally, the reaction produced causes the 4-mm wheal to enlarge, not just to 5 mm, but to a diameter of at least 7 mm. This immediate response is maximal at about 10 to 15 minutes and lasts for up to an hour. It is followed by a late phase, triggered by infiltration into the skin test site of neutrophils and eosinophils, and the release of cytokines and other factors.24 A late phase reaction may cause further enlargement of a positive wheal after 20 to 30 minutes or may cause a previously negative wheal to enlarge (Fig 1). When the results of intradermal testing are being assessed, these reactions should also be noted, if they occur, because they may subsequently interfere with the escalation of and tolerance to immunotherapy. Although a redness, or flare, may occur around intradermal tests performed as part of titration, the experience of Rinkel and most current practitioners has been that the presence and size of the flare is of little clinical value in quantitating the response or guiding immunotherapy based on dilutional intradermal test methods. In SET, one prepares 5-fold dilutions, beginning with a commercially available “concentrate” strength. Dilutions are labeled according to the number of times they have been diluted. Thus, if the concentrate purchased from the antigen supplier is a 1:20-wt/vol mixture, the first dilution, which produces a 1:100 strength, is referred to as the “No. 1 dilution.” The second such 5-fold dilution, producing a 1:500 strength, is the “No. 2”

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Otolaryngology– Head and Neck Surgery October 2003

Fig 2. Normal progressive whealing pattern. The first two tests produce negative wheals, followed by a positive wheal. A stronger concentration produces a confirming wheal. The endpoint is at the No. 4 concentration.

Fig 1. Standard whealing noted with intradermal testing.

dilution, and so on. Many antigens are currently being supplied as “standardized extracts,” and in this case the extract purchased from the antigen supplier is also referred to as the “concentrate,” and dilutions are performed in the same 5-fold manner. The first dilution of the standardized extract would be termed the “No. 1 dilution,” the second would be the “No. 2 dilution,” and so forth. In clinical practice, it is almost never necessary to make (or test with) dilutions weaker than the No. 6 dilution. The underlying principle of SET is that one begins with intradermal testing using an anticipated nonreactive concentration of antigen and then applies progressively stronger concentrations until a reacting strength is confirmed. The strength at which the patient shows a positive wheal size (a wheal of 7 mm diameter or greater) to an individual antigen is referred to as the endpoint of titration and represents the concentration that may safely be used to begin immunotherapy.25 Al-

though most patients react in a linear manner to titration, aberrant whealing responses may occur. In a normal whealing progression, applying progressively stronger concentrations will at some point (in an allergic patient) produce a positive wheal (ie, one that enlarges to a diameter of 7 mm or greater). To confirm that this enlargement of the wheal indeed represents the endpoint of titration, one may apply a test using antigen that is one level more concentrated than that which produced the first positive wheal. This should produce a wheal that is at least 2 mm greater in diameter than the preceding wheal. This is termed the confirming wheal (Fig 2). If, instead of a typical confirming wheal, testing demonstrates a wheal that is the same size as the first positive wheal, this represents a plateau reaction (Fig 3). In such a case, although technically the second such wheal is the one which initiates progressive positive whealing, a more conservative approach may be followed (especially by the novice) in designating the first of the two positive wheals as the endpoint. In other circumstances, one may go from a series of negative wheals to a very large wheal. The etiology of this so-called flash response (Fig 4) is unknown but is postulated to be a result of ingestion by the patient of a cross-reacting food (eg, melons in patients allergic to ragweed). Repeating the test in a few days generally will yield a more conventional response. In the rare circumstance in which persistent flash responses occur, the use of in vitro testing should be considered for diagnosis. Factors affecting skin responses. Before proceeding with skin testing, it is necessary to determine that the skin responds normally to mast cell stimulation but does not exhibit whealing responses to nonantigenic stimuli.26 In one such

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Fig 3. Plateau whealing response. The first two tests produce negative wheals, followed by two identical positive wheals with progressively stronger concentrations. The next stronger concentration produces a confirming wheal. The endpoint is at the No. 4 concentration.

Fig 4. Flash whealing response. The first two tests produce negative wheals, followed by a very large wheal. This often indicates the recent ingestion of a food that crossreacts with the antigen being tested. If retesting in a few days does not provide a clear-cut endpoint, in vitro testing may be indicated.

situation, known as dermatographism, the simple act of placing a needle beneath the skin, or even just scratching it, will produce a wheal-and-flare response. To ensure that this condition is not present, an intradermal test is done with the use of the diluent or some other inert substance. This 4-mm negative control wheal should not enlarge beyond 5 mm. If further enlargement does occur, one must assume that the patient’s skin will not yield accurate results with skin testing but will produce false-positive results. In these instances in vitro testing offers the best avenue for further testing. Antigens are provided in a solution containing 50% glycerin as a preservative. If skin testing is done with the use of dilutions that contain a significant concentration of glycerin, which is a skin irritant, a parallel control of a solution of glycerin alone at the same concentration should be applied, in order to differentiate antigenic from physical whealing produced. This is of practical importance if one is testing with No. 1 or No. 2 antigen

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dilutions, containing 10% and 2% glycerin, respectively. Concentrations of glycerin as small as 0.5% have been shown to slightly increase wheal size over those produced by phenolated saline solution alone,23 but this minor effect at weaker dilutions is of significance primarily in a research setting. Medications affecting skin responses. Numerous medications inhibit the skin whealing response, most notably antihistamines. The antihistamines in current use significantly inhibit whealand-flare responses for 24 hours or more,27 and most clinicians ask patients to avoid all antihistamines and antihistamine-containing compounds for 48 to 72 hours before skin testing. Agents such as loratadine and its metabolite desloratadine can inhibit wheal and flare for up to 7 days.27 Tricyclic antidepressants, such as doxepin and desipramine, suppress wheal responses for 2 to 4 days after their discontinuance.28 Medications that do not significantly affect skin test responses include H2 blockers (eg, ranitidine),29 systemic corticosteroids,30 and leukotriene modifiers.31 To ensure that the wheal-and-flare capability of the patient’s skin is intact, skin testing must include application of a positive control. The skin reacts to a number of nonantigenic challenges, including codeine. However, the most commonly used “positive control” is histamine. For intradermal testing, a 4-mm wheal applied with histamine at a strength of approximately 0.004 mg/mL should yield a 7 mm or larger wheal at 10 minutes. (This dilution of histamine is obtained by making three 5-fold dilutions of a stock solution of histamine, 2.75 mg/5 mL).26 If the application of the histamine control fails to produce a positive response, testing should be suspended for that day, and an investigation into the cause carried out. In all likelihood, one will find that the patient neglected to omit antihistamines before testing, and retesting after 2 to 3 days’ omission will show a positive response to histamine, at which point, further skin tests may be performed. There are other factors that affect skin whealing responses but which are not so critical to the accuracy of test results. These include age and race of the patient, time of day of testing, area of the body to which the tests are applied, the proximity of positive adjacent tests, and ingestion of

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foods that cross-react with the inhalants being tested (ie, “concomitant foods”). Histamine controls or positive skin tests placed too near other test sites can initiate axonal reflexes that drive the wheal-and-flare response. Thus it is recommended that skin test sites be separated by at least 2 cm. The other factors described above affect skin test results so slightly that, other than in research situations, they are of little practical consequence.32 Technique for classic SET. Performance of SET must be preceded by logistic and professional preparation. The logistics include setting up the office, putting the members of the allergy team in place, choosing appropriate antigens, preparing dilutions and controls, and otherwise preparing for testing. The professional preparation, which is much more important, includes the training of every member of the allergy team (physician, nurse and/or technician, and office staff). Each staff member should be aware of the role of allergy in the practice of otolaryngology, the methods by which it is diagnosed and treated, and (probably most importantly) the measures necessary to prevent a reaction to a skin test or injection and to treat such a reaction should it occur. This information is beyond the scope of this monograph but may be acquired by attendance at courses of the AAOA and study of the excellent textbooks available on the subject.33,34 Actual skin testing must be preceded by appropriate evaluation of the patient, including a history, which helps guide in antigen selection. It has been shown repeatedly that testing with a limited number of antigens is both sensitive and specific in determining an individual’s atopic status. Positive tests may, of course, call for additional testing to determine other significant reacting antigens. However, a negative screen may be confirmed with the use of no more than 14 relevant antigens plus appropriate controls.18,19 The tester should wear nonsterile gloves throughout the testing procedure unless he or she and the supervising physician have determined that this measure makes an inadvertent needle stick more, rather than less, likely. Positive and negative controls are first applied. If these control tests do not yield appropriate results, testing should be suspended, as the results of further tests would most likely not be reliable. The arm is

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Fig 5. Position of the syringe in tester's hand for administration of intradermal injection.

marked horizontally from 6 to 2 (representing the dilutions of antigen to be applied) and vertically with abbreviations for the antigens to be tested. Seven antigens may be placed on an upper arm in an average adult so that both arms will provide adequate space for a full testing session. For the novice, a “key” on a sheet of paper may avoid later confusion. Antigens are applied beginning with the No. 6 dilution. The technique of applying the intradermal tests is as follows. Approximately 0.05 mL of antigen is drawn up into an allergy syringe. (Although only 0.01 mL will be injected, the extra amount in the syringe facilitates injection.) Allergy testing syringes have a short bevel, and the needle is attached to the syringe as a single unit, enhancing accuracy of measurement. After preparing the skin with alcohol, the upper arm is grasped with the nondominant hand and the skin drawn tight. The heel of the dominant hand is braced on the patient’s arm, and the needle is held with the thumb and second finger (in the manner of a dart), with the index finger on the plunger (Fig 5). The needle is introduced with the bevel down, penetrating just beneath the skin. The plunger is depressed gently until a 4-mm wheal has been formed. The timer is set to 10 minutes after the first test is applied. After 10 minutes has passed, the diameters of all No. 6 wheals are measured and the results (in millimeters) are entered on the titration sheet (Table 2). If a negative wheal results from testing at the

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Table 2. Sample full titration with SET (endpoint in parenthesis) Wheal diameter (mm)

Antigen Bermuda Timothy Ragweed Lamb’s quarters Marsh elder Oak Elm Mountain cedar Alternaria Cladosporium Helminthosporium D farinae Cat Controls Diluent Glycerine No. 2 Histamine No. 3

No. 6

No. 5

No. 4

5 (7) 5 5 5 5 5 5 5 5 5 5 5

(7) 9 5 5 5 5 5 5 (7) 5 (7) 5 (8)

9 5 5 5 5 7 5 9 (8) 9 5 11

No. 3

5 5 5 (8) (7) 5 10 5

5 5 7

The total number of sticks, including controls, was 49.

No. 6 level for an antigen, progressively stronger concentrations of that antigen (ie, Nos. 5, 4, 3, and 2) are applied until a positive wheal is obtained. A positive wheal is one that grows at least 2 mm larger than the 5-mm wheal that results from placement of a 4-mm test wheal. The first concentration of antigen that produces a positive wheal is termed the endpoint of titration and represents the concentration of that antigen at which immunotherapy may safely be begun. To confirm that the endpoint has truly been reached, Rinkel urged the placement of a skin test by using an antigen one dilution more concentrated than the one that produced the endpoint wheal.25 If the wheal that results is ⱖ2 mm or greater in diameter than the endpoint wheal. This is referred to as a confirming wheal. Antigens are tested up to the No. 2 dilution. If no positive wheal occurs by that point, most clinicians will end the test. Optimizing the efficiency of intradermal titration. It is apparent that doing a full titration,

from No. 6 to No. 2, with 14 antigens used as an initial screen, could require up to 70 needle sticks, plus appropriate controls. Furthermore, if even a conservative battery of 25 inhalant antigens is used for testing before immunotherapy, up to 125

needle sticks might be used. Although this sequential dilutional testing reflects the most accurate means of determining the degree of sensitivity to each antigen, it also is impractical for most modern practitioners because of time constraints. Therefore, over the years, a number of measures to make SET more efficient have been developed and have proved to be both safe and effective when practiced by those who are thoroughly familiar with the basis and nuances of SET. These principles form the basis of modern IDT, as well as other modified testing approaches. One of the benefits of SET is that it allows the accurate prediction of a safe starting dose for immunotherapy for various antigens35 regardless of the patient’s current ambient exposure to those antigens. It has been established that “in season,” patients exhibit symptoms and mediator release from smaller allergen challenges than were required to produce the same effect before continued allergen exposure began.36 Some patients are considered “brittle” or “labile”—that is, they are more likely to exhibit a significant reaction to skin testing, possibly including systemic symptoms such as anaphylaxis. Members of this category include patients with asthma (especially steroid-dependent patients), those receiving ␤-blocker medication,37 and those with a history of previous significant reactions to skin testing or immunotherapy. These patients, as well as those being tested for antigens that are “in season” or to which they have recently had significant exposure, should always have testing initiated with a No. 6 dilution. As a general practice, however, it is safe to begin testing all other patients at a No. 4 dilution to limit the number of needle sticks necessary for testing. Both the inexperienced otolaryngic allergist beginning practice and all otolaryngic allergists beginning a practice in a new geographic location should consider initiating their testing with a No. 6 dilution until acquiring adequate experience to safely modify their testing approach. The methodology that follows relies on an appreciation and understanding of the normal and abnormal whealing responses encountered during classic SET. If one recognizes that a negative skin test is one in which a 4-mm wheal grows to no more than 5 or 6 mm in diameter whereas a

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Table 3. Sample titration with optimized IDT (EP in parenthesis) Wheal diameter (mm)

Antigen Bermuda Timothy Ragweed Lamb’s quarters Marsh elder Oak Elm Mountain cedar Alternaria Cladosporium Helminthosporium D farinae Cat Controls Diluent Glycerine No. 2 Histamine No. 3

No. 6

No. 5

No. 4

5 (7)

(*)

9

5 5 (*) (*) (*)

5 5 5 5 (7) 5 9 (8) 9 5 11

No. 3

(*)

5 5 7

Titration performed in spring, when grass and trees are in season, so these are started at No. 6. EP indicated by asterisk is estimated based on wheal size at stronger dilution. Note that all EPs are the same as in the previous table except for cat, which is started one dilution weaker than true EP. The total number of sticks, including controls, was 19.

positive “endpoint” wheal grows to 7 mm or more and that testing with one concentration stronger than the one that produced the endpoint response generally yields a wheal of 9 mm diameter or greater, it is possible to extrapolate and “fill in the blanks” of a titration that does not necessarily involve placing a skin test with the use of every possible dilution (Table 3). For example, if testing a patient who does not fit the criteria noted above of a “brittle” patient, one could apply a No. 4 dilution. If the wheal produced grew to 9 mm, extrapolation would suggest that the endpoint was at No. 5. This could be confirmed, if desired, by placing a No. 5 dilution to produce a wheal of approximately 7 mm in diameter. If testing at a No. 4 dilution produced a negative wheal, a test at No. 2 strength would be applied. If the wheal produced by the No. 2 dilution grew to 7 mm in diameter, one could assume that the endpoint was at No. 2, whereas a negative wheal at this concentration would indicate a negative titration for this antigen. Although the placement of a confirmatory wheal was suggested by

Rinkel to verify the specific endpoint of titration and to reduce the incidence of false-positive reactions derived from single dilutional intradermal testing,25 in most cases it is not absolutely necessary. Testing based on the classification of a 7-mm wheal as positive without a confirmatory wheal will rarely yield results that differ significantly from those obtained through requiring a 9-mm confirmatory wheal. Furthermore, this approach will not adversely affect the safe provision of immunotherapy. If the skilled clinician elects to eliminate the confirmatory wheal from the IDT battery, it will decrease both the number of needle sticks and the time necessary to complete the testing. With the use of a 14-antigen screen and testing in the fashion described above, it is possible to confirm a negative titration with no more than 30 sticks, including controls. Additional efficiency may be achieved by combining this optimized IDT technique with other methodologies. Benefits of intradermal titration. The quantitative methodology of IDT allows identification of both low and high degrees of sensitivity and provides information about a safe starting dose for immunotherapy in both instances. The antigens included in the treatment set are generally taken from the stock vials used to prepare the material from which the testing was done, so each patient’s response to them has already been assessed by a bioassay. Although sensitivities change with antigen exposure, IDT assesses the patient’s current degree of sensitivity, either in or out of season. Although circumstances and constraints may make it impractical to perform a full titration on every patient, the principles of quantitative testing and development of a treatment regimen tailored to each individual patient remain central to the practice of otolaryngic allergy. Modified Quantitative Testing As demonstrated above, IDT offers a thorough, comprehensive, quantitative approach to skin testing for inhalant allergy. It is safe, because it progresses gradually from weaker to more concentrated antigenic solutions, at the same time permitting precise, quantifiable measurement of allergic sensitivities. The increased commitment in testing time and costs that is associated with clas-

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sic SET is partially offset by using the optimized form of IDT just described. Recognizing that quantification is important in determining safe and effective starting doses for immunotherapy, but also considering the time and financial constraints of IDT, methods have more recently been sought to modify the testing method described above while maintaining its ability to discriminate quantitatively. Several approaches have been developed in order to reach an appropriate compromise between efficiency and accuracy. One such approach is modified quantitative testing (MQT). This technique uses prick testing initially to determine an approximate range of sensitivity, with a single weaker or more concentrated intradermal test used to define the level of sensitivity and quantify the allergic response. One consideration that is important in the use of prick testing techniques is that not all prick testing methods or devices are equivalent. Some prick testing devices provide more replicable results than others, and the sensitivity and specificity of testing with these various devices vary.38,39 In general, those prick devices that allow reproducible delivery of a standard amount of antigen to a uniform depth within the epidermis are preferable to those devices that are less reproducible. The best current prick instruments are multipronged devices that do deliver a reproducible amount of antigen to a controlled depth. These devices have been shown to be less technician-dependent than the Morrow-Brown needle, with results that are therefore more reliable and reproducible.40 With these multipronged devices, several antigens can be placed on the skin simultaneously, with precision in both the amount of antigen that is delivered and the depth of delivery. These multipronged devices have accompanying testing wells that contain antigen concentrate into which the devices are placed before testing. They also have multiple fine tines in which a precise amount of antigen concentrate is held by capillary action. The device that was used in MQT as originally described is the Multi-Test II device (Lincoln Diagnostics, Inc, Decatur, IL), although other devices, such as the Quintest device (Hollister-Stier Laboratories, LLC, Spokane, WA) may be used as well.

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Fig 6. Placement of antigens into forearm with Multi-Test device.

Technique of MQT. The patient is brought into the testing room and properly identified. The patient is then questioned concerning the use of any medications that may adversely affect either the accuracy or the safety of the test. These medications include ␤-blockers, tricyclic antidepressants, and antihistamines. Both the volar surface of the forearms and the upper outer aspects of both arms are used for testing, so these areas are exposed. The forearms are first cleaned with alcohol, and ink is used to mark the location and orientation of the testing punctures that will be placed. The antigens to be tested have been previously positioned in testing wells in a discrete pattern so that they can be identified after they have been placed on the skin. Both a positive (histamine) control and a negative (saline solution) control are included in the testing board. If there is any question about the skin’s ability to respond to testing (as with a patient in whom current histamine blockade is unknown), an individual prick test with histamine may be placed before full testing. The test antigens are then placed onto the forearm with moderate pressure and a gentle rocking motion both from side to side and from forward to backward (Fig 6). As the device is taken off the skin, small droplets of antigen will remain at the individual testing sites and should not be wiped clean for at least 5 minutes. Patients should be advised to keep their arms relatively immobile during those 5 minutes to prevent cross-contamination of antigens. For screening purposes, 1 Multi-Test II device of 8 tests may be placed on each volar forearm. For any additional testing, up to 2 panels of 8 tests each, may be placed on each

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Fig 7. Skin whealing results with Multi-Test device.

volar forearm, for a total of 30 antigens and 2 controls. (In young children there may not be adequate surface area to allow use of 2 devices on each forearm, and testing may need to be conducted on either the anterior thigh or the back.) After placement of the tests, 20 minutes are allowed for the wheals to develop at the site of each test. The wheals are then measured and their size recorded. A positive test is defined as a wheal with a diameter of 3 mm or greater at 20 minutes, consistent with the guidelines of the European grading systems (Fig 7). If all tests show whealing, as may occur with a dermatographic patient or with a patient who is overly sensitive to the trauma of the puncture, a positive wheal is defined as a wheal with a diameter of 3 mm or greater than the diameter of the negative control wheal. All positive test responses are then circled on the recording sheet for ease of identification. On the basis of whether the prick test is negative, a single intradermal test of either a No. 2 dilution (1:500 wt/vol) or a No. 5 dilution (1: 62,500 wt/vol) is then placed on the upper outer arm. The previous experience of Murphree and Kniker40 with this testing technique suggests that the level of response to the Multi-Test device approximates that of a 1:1,500 wt/vol intradermal test, approximately corresponding to a No. 3 dilution SET test. MQT is designed to further refine this initial estimate of sensitivity through use of intradermal tests with either stronger or weaker concentrations of antigens. These intradermal tests can then be used to estimate dilutions of antigen with an IDT model and therefore to provide a

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quantitative basis for the provision of immunotherapy. In practice, once the prick testing results are recorded, a single intradermal test is then applied for each of the antigens tested. If the prick response for a specific antigen is negative (⬍3 mm wheal), a single 4-mm intradermal wheal with a No. 2 dilution of that antigen is applied to the upper outer arm. If the prick response is positive (ⱖ3 mm wheal), a single 4-mm intradermal wheal with a No. 5 dilution of that antigen is applied to the upper outer arm. A positive response to intradermal testing is a wheal of 7 mm or greater in diameter at 10 minutes. On the basis of the results of these intradermal tests, an approximate endpoint can be determined that can be used to prepare treatment vials for immunotherapy. Application of these results is noted in the MQT algorithm shown in Fig 8.41,42 The one exception to this two-stage procedure is in the case of a large response to the initial prick test. By definition, a response of 9 mm or greater in whealing to the initial prick test would be assigned an endpoint value of No. 6, and no intradermal test would be placed. By reference to the algorithm (Fig 8), a response to an individual antigen that is negative to both the initial prick test and to the No. 2 intradermal test is classified as a negative response to that antigen. A response to an individual antigen that is negative to the initial prick test but positive to the No. 2 intradermal test is classified as an endpoint of No. 3. A response to an individual antigen that is positive to the initial prick test and negative to the No. 5 intradermal test is classified as an endpoint of No. 4. A response to an individual antigen that is positive to the initial prick test and positive to the No. 5 intradermal test with a wheal size of 7 or 8 mm is classified as an endpoint of No. 5. A response to an individual antigen that is positive to the initial prick test and positive to the No. 5 intradermal test with a wheal size of 9 mm or greater is classified as an endpoint of No. 6. These endpoints are considered to correspond to the endpoints obtained with a full, standard SET battery with the use of several sequential intradermal tests, and dose calculation and vial preparation for immunotherapy are approached in the same manner.

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Fig 8. MQT algorithm.

Because MQT uses IDT as the final step in quantifying the patient’s sensitivity, it can appropriately be classed as one form of IDT. Prick/Puncture Testing Epicutaneous tests were among the earliest tests used for the diagnosis of inhalant allergy. These techniques can be divided into scratch tests, in which a superficial cut is made into the epidermis and antigen is applied to the denuded skin, and prick/puncture tests, in which a drop of antigen is introduced into the epidermis through a superficial needle prick or puncture. Scratch testing, which has been noted to have both poor sensitivity and poor specificity, is mentioned here for historical purposes only. Because of its poor clinimetric properties and the availability of more accurate techniques, the AMA Council on Scientific Affairs long ago recommended against the use of this outmoded technique.43 For the purposes of this monograph, all prick/ puncture techniques, whatever device is used for their application, will be generically referred to as prick tests. Prick testing is in routine use throughout the world, often without intradermal testing, for the diagnosis of allergy and the provision of immunotherapy. This therapy, however, involves empiric dosing, rather than being based on quantitative information such as is available through IDT. Several specific methods have been de-

scribed for conducting prick tests. Single-antigen prick devices include lancets, the Morrow-Brown needle (Antigen Laboratories, Inc, Liberty, MO), and the DuoTip device (Lincoln Diagnostics, Inc). For all types of prick testing (except those which use a multiple prick applicator, the technique for which has already been described), the patient is first brought into the testing room and properly identified. The patient is then questioned concerning the use of any medications that may adversely affect either the accuracy or the safety of the test, including ␤-blockers and antihistamines. Testing may be done on the upper back, the volar surface of the forearms, and/or the upper outer aspects of both arms. The physician must be aware that not all anatomic sites demonstrate the same degree of skin reactivity. In general, the most brisk skin reactions will be found on the upper back, which is why this site was often chosen for skin testing when scratch techniques were used. In decreasing order, the degrees of reactivity are as follows: mid and upper back ⬎ lower back ⬎ upper arm ⬎ elbow ⬎ forearm (ulnar ⬎ radial) ⬎ wrist.44 These areas are exposed as indicated. The skin is first cleaned with alcohol, and ink is used to mark the location and orientation of the testing pricks that will be placed. With the lancet devices, a small drop of antigen concentrate (1:20 wt/vol or standardized antigen

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concentrate) is placed onto the skin and this solid needle is then used to elevate or “tent” the skin through the drop of antigen, taking care not to penetrate into the dermis. The Morrow-Brown needle can also be used to introduce antigen into the skin. With this technique the needle is placed through the antigen drop perpendicular to the skin. The depth of penetration is controlled by a small flange on the shaft of the needle. Several grading systems are available for evaluating the response, ranging from a 1⫹ to 4⫹ system in which both wheal and flare (erythema) are used to grade the response, to measuring and recording the size of the wheal to reflect the degree of reactivity. These responses are read for each individual antigen at 10 minutes after placement. The technique is subject to some variation of depth of penetration, and thus the intensity of the wheal-and-flare reaction may also vary. For that reason, lancet-based techniques have grown less popular. To improve the reliable and objective measurement of testing results, the use of wheal measurements for assessment of skin reactivity is preferred. The degree of erythema (flare) is considered to be a nonspecific reaction of the skin to the trauma of the puncture and should not be used in the assessment or measurement of the degree of antigen-specific sensitivity. A wheal that grows to a diameter of ⱖ3 mm greater than a negative control is judged to be positive. The diameter of the wheal is recorded for each antigen tested. A bifurcated needle such as the DuoTip can also be used for prick testing of single antigens. This device allows a small but reproducible amount of antigen to be held by capillary action within its two tines so that the antigen is applied to the skin concurrent with the puncture of the skin. Individual devices are placed in testing wells containing antigen concentrate and are removed individually at the time of testing. Each device is individually placed vertically on the skin, and with uniform pressure to slightly indent the skin, the device is rapidly rotated through 360°. This procedure provides a precise amount of antigen to be delivered to a uniform depth. As with the Morrow-Brown needle, the test sites are read at 10 minutes for skin reactivity. Again, a wheal that grows to a diameter of ⱖ3 mm greater than a negative control is

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judged to be positive. The size of the wheal is recorded for each antigen that is tested. Once prick testing has been completed for all antigens, the testing results are used to determine the contents of the treatment vial if immunotherapy is contemplated. Prick tests, as a group, lack the degree of quantitative information that is available with either IDT or MQT. Given that only the whealing response to one discrete concentration of antigen has been assessed, it can be difficult to prepare a treatment vial that will be potent enough to provide efficient escalation of immunotherapy doses yet maintain the degree of safety inherent in quantitative testing approaches. This factor is the major issue that is of concern in delivering immunotherapy on the basis of prick testing alone. Despite this caution, it is possible to deliver immunotherapy on the basis of a single prick test with each antigen. This practice is common in both Europe and the United States, even among clinicians who use single intradermal tests in addition to prick tests. Several considerations are important in considering immunotherapy based on prick testing. First, the standard method by which many allergists use prick-based immunotherapy is through preparing treatment vials with all antigens to which a patient has reacted at extremely dilute concentrations, such as 1:1,000,000 wt/vol. Although these dilutions will likely be safe, this approach will require many months before the antigen levels are adequate to promote an immune response that will result in symptomatic improvement. In addition, because the degrees of sensitivity to various antigens will likely differ among antigens, preparation of immunotherapy vials with uniform concentrations of antigens will tend to result in adverse local and systemic reactions to some antigens that will limit even a minimal therapeutic response to other antigens. It is this observation that has guided otolaryngic allergy practice from the outset and led early clinicians such as Hansel and Rinkel to develop SET. To achieve a very rough quantification of testing results, some practitioners divide testing results into two or more categories of response levels— high- and low-sensitivity responses— on the basis of wheal size. They then use two different dilutions of antigen in preparation of immunotherapy vials. One such approach involves dividing

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positive responses into (1) low-level responses, with wheal sizes of ⱖ3 mm but ⱕ8 mm, and (2) high-level responses, with wheal sizes of ⱖ9 mm. The assumption here is that the degree of responsiveness on the skin provides an estimate of the amount of antigen that is necessary to provoke a certain level of response. With this two-level system, two different dilutions of antigens can then be used in vial preparation. In the first group, the low-level antigen responses, a conservative estimate would be to classify these as positive at IDT dilution No. 4, or 1:12,500 wt/vol. The second group, the high-level responses, would then be classified conservatively as positive at an IDT dilution No. 6, or 1:312,500 wt/vol. It must be emphasized that this approach is semiquantitative and does not provide the precision (or safety) achieved with the quantitative methods already described. Although immunotherapy vials for use in desensitization are often prepared from prick testing results alone by experienced allergists, this technique should only be used with extreme caution by novices or inexperienced physicians. Second, the provision of safe immunotherapy relies on the use of a vial test before treatment with the initial set of immunotherapy vials. The use of a vial test is strongly recommended with IDT and is mandatory with MQT and all prick testing, as it is with in vitro testing. The vial test involves the raising of a 4-mm intradermal wheal with each immuno therapy vial that has been prepared. If the wheal grows to greater than 13 mm in diameter at 10 minutes, the vial is overly concentrated and must be diluted 5-fold before beginning immunotherapy. If the wheal is less than 13 mm in diameter at 10 minutes, immunotherapy can be initiated at that time, and if the wheal is precisely 13 mm, the initiation of immunotherapy is deferred until the following treatment visit, at least 72 hours later than the time of the vial test. With care to detail and with the added safety of the vial test, immunotherapy based on prick testing alone can be safe and effective in the treatment of inhalant allergy. When patients do not respond to immunotherapy conducted with prick testing alone after a reasonable period of time (3-6 months), it would be prudent to consider retesting the patient with a more thorough, quantitative approach in order to assess whether some low-

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level sensitivities may have been missed with prick testing. Consideration of full IDT or intradermal testing based on the MQT algorithm (Fig 8) and the results of the initial prick testing would be acceptable in these patients. SUMMARY The otolaryngic allergist has a variety of skin testing methods available for the diagnosis of inhalant allergy. The precise technique or techniques that each physician will select will depend on his or her individual practice characteristics and his or her familiarity with and confidence in those available methods. The AAOA, in its 2003 principles for the diagnosis of inhalant allergy, has recognized that there is no one method that will meet the needs of all patients or physicians. There is little question that a full SET titration provides the most information of any type of skin test, but because of various factors (some, unfortunately, socioeconomic), it is rarely feasible. With the use of an optimized approach through IDT, information may be gained that will often suffice. Screening with prick tests and then achieving quantification through MQT is another effective alternative. Treating from prick test results alone may be appropriate in the hands of experienced practitioners, although novices should realize its lack of precise quantification. No one method will be applicable in every circumstance, and the otolaryngic allergist should strive for familiarity with all techniques. As is generally noted in the practice of medicine, it is the flexible application of many techniques chosen for use in individual circumstances with individual patients that allows the successful treatment of complex medical illnesses. Otolaryngic allergy cannot be practiced by rote and flow sheet. In order to practice otolaryngic allergy safely and effectively, it is important for every otolaryngic allergist to understand the science of immunology as it relates to IgE-mediated hypersensitivity, the relevant pharmacology of agents used to treat these illnesses, and the anatomy and physiology of the nose and paranasal sinuses. The practice of otolaryngic allergy can at times be more an art than a strict science, but without a thorough working knowledge of the relevant basic and clinical sciences underlying its

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practice, the physician will likely experience suboptimal treatment outcomes for his or her patients. This monograph has been designed to summarize the available types of skin testing concisely so that otolaryngic allergists may use them in the management of their patients. It is not meant to be a substitute for the excellent journal articles and textbooks that discuss this topic in greater depth. It is hoped that it will serve as a springboard for additional reading and study. The practice of otolaryngic allergy is fluid and dynamic, and it is necessary for each of us to continue to study, learn, and critically analyze our methods and our knowledge base for the benefit of the specialty and, more importantly, for the health and welfare of our patients. REFERENCES

1. Wyman M. Autumnal catarrh. Cambridge: Hurd & Houghton; 1872. 2. Blackley CH. Experimental researches on the causes and nature of Cattarrhus aestivus. London: Balliere, Trindall, & Cox; 1873. 3. Hurst DS, Gordon BR, Fornadley JA, et al. Safety of home-based and office allergy immunotherapy: a multicenter prospective study. Otolaryngol Head Neck Surg 1999;121:553-61. 4. Rinkel HJ. The management of clinical allergy: III inhalant allergy therapy. Arch Otolaryngol 1963;77:205-25. 5. Trevino RJ. Comparison of results of immunotherapy based on skin end-point titration, prick testing, and scratch testing. Otolaryngol Head Neck Surg 1994;111: 550-2. 6. Krouse JH, Krouse HJ. Efficacy of immunotherapy based on skin end-point titration. Otolaryngol Head Neck Surg 2000;123:183-7. 7. Lee LK, Kniker WT, Campos T. Aggressive coseasonal immunotherapy in mountain cedar pollen allergy. Arch Otolaryngol 1982;108:787-94. 8. Council on Scientific Affairs (AMA). In vivo diagnostic testing and immunotherapy for allergy. JAMA;1987: 1363-7. 9. American Academy of Allergy, Asthma, and Immunology. Position statements: Controversial techniques. 8. J Allergy Clin Immunol 1981;67:333-8. 10. Nelson HS, Oppenheimer J, Buchmeier A, et al. An assessment of the role of intradermal skin testing in the diagnosis of clinically relevant allergy to timothy grass. J Allergy Clin Immunol 1996;97:1193-201. 11. Menardo JL, Bosquet J, Michel FB. Comparison of three prick test methods with the intradermal test and with the RAST in the diagnosis of mite allergy. Ann Allergy 1982;48:235-9. 12. Schwindt DA, Hutcheson PS, Dykewicz MS. Positive intradermal tests with corresponding negative percutaneous tests fail to identify clinically relevant respiratory allergy assessed by nasal challenges. Paper presented at the annual meeting of the American Academy of Allergy,

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32. Nelson HS, Knoetzer J, Bucher B. Effect of distance between sites and region of the body on results of skin prick tests. J Allergy Clin Immunol 1996;97:596-601. 33. King HC, Mabry RL, Mabry CS. Allergy in ENT practice: a basic guide. New York: Thieme; 1998. 34. Krouse JH, Chadwick SJ, Gordon BR, Derebery MJ. Allergy and immunology: an otolaryngic approach. Philadelphia: Lippincott-Williams and Wilkins; 2002. 35. Smith TF. Allergy testing in clinical practice. Ann Allergy Asthma Immunol 1992;68:293-302. 36. Connell JT. Quantitative intranasal pollen challenge. II. Effect of daily pollen challenge, environmental pollen exposure and placebo challenge on the nasal membrane. J Allergy 1968;41:123-39. 37. Toogood JH. Risk of anaphylaxis in patients receiving beta-blocker drugs. J Allergy Clin Immunol 1988;81:1-5. 38. Nelson HS, Lahr J, Buchmeier A, et al. Evaluation of devices for skin prick testing. J Allergy Clin Immunol 1998;101:153-6. 39. Mahan C, Spector S, Siegel S, et al. Validity and repro-

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