The importance of quantifying skin reactivity in treating allergic rhinitis with immunotherapy.

Abstract

Therapeutic options for the treatment of allergic rhinitis include environmental modifications to decrease exposure to allergens, pharmacotherapy, and immunotherapy for those patients who do not experience satisfactory relief of their symptoms with medical management. Skin testing is the best established and most sensitive indicator of allergic disease. Several techniques are currently in use to identify pertinent antigens in the treatment of inhalant allergies. We describe the various skin testing techniques that are associated with such inhalant allergies. Quantification of skin reactivity to formulate a successful antigen vial for effective immunotherapy is necessary in the management of allergic disease.

Introduction

Allergic rhinitis is the fifth most prevalent chronic condition in the United States, affecting an estimated 36 million Americans and accounting for approximately 3 million lost work days and 2 million lost school days. [1-3] The economic impact of allergic rhinitis in the United States is high by any standard. According to one population survey, the estimated cost of physician visits and medications is $3.5 billion annually. [4]

Allergic rhinitis is an inflammatory condition characterized by an immunoglobulin E (IgE) -mediated reaction to airborne allergens that results in inflammation of the nasal mucosa and other target organs. Approximately 50% of the patients encountered by otolaryngologists have some type of allergy as a major cause of, or at least a contributing factor in, the problem that prompted their visit. Because the head is the most common portal of entry ("the shock organ") for inhalant sensitivities--and considering the associated disorders (chronic or recurrent rhinosinusitis, otitis media, laryngitis, and vertigo)--the otolaryngologist is uniquely qualified by way of medical and surgical training to diagnose and select the most appropriate and effective means of managing upper respiratory allergic disease.

Medical therapeutic options for allergic rhinosinusitis include environmental control, decongestants, antihistamines, other antimediator drugs, and immunotherapy. Immunotherapy is indicated for those patients who do not experience sufficient symptom relief medically. It is important to note that the goals of allergy testing and immunotherapy include the accurate identification and quantification of each antigen to which the patient is allergic so that the therapeutic approach can be designed to provide symptom relief in a safe and expedient manner.

Successful immunotherapy is defined by a decrease in a patient's allergic reactivity and by the relief of symptoms of an IgE-mediated allergy. Although several theories have been proposed to explain the clinical efficacy of immunotherapy, the exact mechanisms by which it is effective are not completely understood, and they are the subject of much debate. It is known that a decrease occurs in circulating allergen-specific IgE even when there is a temporary rise early in the course of immunotherapy. [5] This effect can be secondary to the suppression of T-helper cells or the excitation of T-suppressor lymphocytes in modulating the formation of IgE. [6] It is also believed that the formation of immunoglobulin-G-blocking antibodies (specifically IgG4) is correlated with successful allergy management because an increase in specific IgG4 has been associated with a good clinical response by some investigators. [7] However, there is no definitive conclusion regarding these antibodies because other studies have not c onfirmed these findings. [8] Regardless of what its direct immunologic effects are, immunotherapy is an effective management tool in the treatment of allergic rhinosinusitis. Because the effectiveness of immunotherapy does not occur independently of the diagnostic methodology, herein we describe the various types of testing techniques for inhalant allergies.

Skin testing techniques

Skin testing is the best-established and most sensitive indicator of allergic disease. It relies on the reactivity and sensitivity of mast cells that have been sensitized with specific IgE to reflect allergen sensitivity. Skin testing involves introducing specific antigens onto or into the skin by way of scratch, prick, and intradermal tests.

Scratch testing. Scratch testing is insensitive, painful, not reproducible, and no longer a recommended diagnostic procedure. [9]

Prick testing. Prick tests were first described by Lewis and Grant in 1926, [10] and they were popularized by Pepys in the 1970s. [11] Prick tests are superior to scratch tests because they are more sensitive, more reproducible, and correlate better with intradermal tests. [12] They can be performed in a variety of ways, but the type of testing greatly influences the results.

In general, the technique involves introducing a predetermined strength of antigen (usually concentrate) into the skin and interpreting the wheal-and-flare response after 10 to 20 minutes. This response is graded from 0 to 4+, depending on the size of the wheal and the degree of erythema. The classic prick test was first performed with a 25-gauge hypodermic syringe needle. [13] The needle was introduced about 1 mm deep into the skin at an angle through a droplet of antigen. The skin was then lifted and tented to allow more antigen entry. This procedure is subject to significant variability because of the difficulty of precisely reproducing the depth of penetration, the amount of force used, and the amount of skin lifting.

The vertical prick puncture with a single point was developed by Brown et al in an attempt to better standardize prick tests. [14] This procedure involves using a guard that prevents penetration of the needle into the skin beyond a predetermined depth; also, no skin lifting is used. Other puncture tests have been developed in an effort to control the variability of prick testing, yet detectable differences remain in the reproducibility among them. [15] More recently, multiprick devices have been developed that are believed to be more sensitive and less technique-dependent than single prick tests. [16]

The major disadvantages of prick testing are the lack of standardization and the lack of quantification. This test does not determine the precise level of sensitivity for specific antigens. In addition, it misses low-sensitivity responses because there is no opportunity to detect allergic disease at sensitivities below the concentration of the antigen that is used. Because of this lack of quantification, immunotherapy based on skin prick testing must be started at doses sufficiently diluted to minimize the possibility of a systemic reaction. Antigens appropriate for inclusion in therapy are generally divided into high- and low-sensitivity groups based primarily on the reaction observed during prick testing. All low-sensitivity antigens are mixed at an identical concentration (usually 1:20,000 w/v), and those that are believed to be high-sensitivity antigens are then mixed in a separate vial at concentrations of 1:200,000 w/v. The antigens are further diluted in direct proportion to the number of antigens pla ced in each treatment vial.

One drawback associated with treatment based on prick testing is the length of time required to achieve maximum dosing; months to years might be needed to reach these levels. Moreover, because of the different antigen sensitivities, a therapy-limiting response from one antigen will occur while other antigens in the same treatment vial will remain at far-from-optimal dosages. Failure to reach therapeutic concentrations for all pertinent antigens will result in a lack of allergic symptom relief and treatment failure.

Intradermal testing. Skin endpoint titration (SET) testing, also referred to as serial dilution quantitative intradermal testing, is a modification of intradermal testing that uses specific antigen dilutions to establish the minimum amount of antigen required to produce a positive skin test. SET differs from other skin tests in that it is primarily designed to be a quantitative rather than a qualitative test of allergen sensitivity. Although it is possible to perform semiquantitative skin testing with prick techniques, [17] it is not commonly done because the range of testing is technically limited by the high concentrations of antigen required for these epicutaneous tests.

SET uses a 1:5 dilution of antigens. The physician starts with a concentrate (1:20 w/v) and sequentially dilutes it in fivefold increments, which by convention have been labeled dilution No. 1 (1:100), dilution No. 2 (1:500), dilution No. 3 (1:2,500), dilution No. 4 (1:12,500), dilution No. 5 (1:62,500), and dilution No. 6 (1:312,500).

The procedure begins with the injection of a very dilute mixture (usually dilution No. 6) into the skin, which creates a 4-mm wheal that grows to 5 mm by diffusion. The wheal is observed for 10 minutes. If the wheal does not enlarge by at least 2mm (i.e., from 5 to 7mm), the next stronger dilution (dilution No. 5) is injected and the wheal is again observed for growth. This process is repeated until a 2-mm wheal growth is observed. Confirmation that the correct concentration has been identified is obtained when the next more-concentrated dilution increases the size of the wheal by an additional 2 mm (i.e., from 7 to 9 mm) within 10 minutes ("the confirmatory wheal"). The "endpoint" is defined as the first wheal that increases in size by 2 mm, followed by a confirmatory wheal. The endpoint concentration identifies not only the antigens to which the patient is allergic, but also the patient's level of sensitivity to them, providing a safe point for the initiation of immunotherapy. The endpoint does not correla te with symptomatology, and it does not predict the maintenance dose of therapy.

Once the different antigens have been evaluated for reactivity in this manner, a treatment vial can be created that will include each clinically pertinent antigen at its individual endpoint concentration. Immunotherapy is usually started with an intradermal test dose of 0.05 ml from the treatment vial, followed by weekly injections escalating by 0.05 ml each time until the symptom-relieving dose (the highest dose of antigen that provides maximum relief of symptoms without producing any significant local or systemic reactions) is achieved. [18]

The advantages of SET are its ability to: 1) deliver antigen at a safe concentration, but close to the maximum tolerated level at the onset of treatment, 2) shorten the length of time needed to achieve symptom relief, and 3) provide a way to increase the concentration of each antigen based on the individual level of sensitivity. This technique thereby avoids the chance that a particularly high-sensitivity antigen will cause a local or systemic reaction during dose escalation, which would limit the progression of the entire series before therapeutic levels are attained for other important but less-sensitive antigens.

Quantification of skin reactivity by intradermal testing with the SET technique provides the most accurate assessment of a patient's hypersensitivity. For an antigen to elicit a beneficial immunologic response, it must be administered in large enough doses to stimulate a therapeutic response. [19] Only those skin tests that can quantify the patient's sensitivity to each individual allergen will provide the information necessary to formulate a treatment program that will achieve optimal therapeutic results. [20] The methodology used in skin testing has a direct relationship on our ability to identify the optimum therapeutic dosage of each antigen and therefore to achieve the ultimate success with immunotherapy.

From the Department of Otolaryngology, Louisiana State University, Shreveport (Dr. Trevino), and the Division of Otolaryngology, Department of Surgery, University of Louisville (Ky.) School of Medicine (Dr. Veling).

Reprint requests: Richard J. Trevino, MD, 280 N. Jackson Ave., Suite C, San Jose, CA 95116. Phone: [phone]; fax: [phone].

References

(1.) Nathan RA, Meltzer EO, Selner JC, Storms W. Prevalence of allergic rhinitis in the United States. J Allergy Clin Immunol 1997;99(Suppl):S808-S814.

(2.) Collins JG. Prevalence of selected chronic conditions: United States, 1986-88. Vital and Health Statistics. Hyattsville, Md.: Public Health Service. U.S. Department of Health and Human Services Publication (PHS 93-1510, series 10, No. 182), 1993.

(3.) U.S. Department of Health and Human Services. Asthma and allergies: An optimistic future. Bethesda, Md.: National Institutes of Health (Publication No. 80-388), 1980.

(4.) Storms W, Meltzer EO, Nathan RA, Selner JC. The economic impact of allergic rhinitis. J Allergy Clin Immunol 1997;99 (Suppl):S820-S824.

(5.) Zeiss CR, Metzger WJ, Levitz D. Quantitative relationships between IgE antibody and blocking antibodies specific for antigen E in patients given immunotherapy with ragweed antigen E. Clin Exp Immunol 1977;28:250-5.

(6.) Rocklin RE, Sheffer AL, Greineder DK, Melmon KL. Generation of antigen-specific suppressor cells during allergy desensitization. N Engl J Med 1980;302:1213-9,

(7.) Ohashi Y, Nakai Y, Okamoto H, et al. Significant correlation between symptom score and IgG4 antibody titer following long-term immunotherapy for perennial allergic rhinitis, Ann Otol Rhinol Laryngol 1997;106:483-9.

(8.) Djurup R, Mailing HJ. High IgG4 antibody level is associated with failure of immunotherapy with inhalant allergens. Clin Allergy 1987;17:459-68.

(9.) In vivo diagnostic testing and immunotherapy for allergy. Report I, Part I, of the allergy panel. Council on Scientific Affairs. JAMA 1987;258:1363-7.

(10.) Lewis T, Grant RT. Vascular reactions of the skin to injury. Heart 1926;13:219-25.

(11.) Pepys J. Skin testing. Br J Hosp Med 1975;10(Suppl):1-59.

(12.) Nelson HS. Diagnostic procedures in allergy. I. Allergy skin testing. Ann Allergy 1983;51:411-8.

(13.) Pepys J. Skin tests in diagnosis. In: Gell PGH, Coombs RRA, Lachmann PJ, eds. Clinical Aspects of Immunology. 3rd ed. Oxford: Blackwell Scientific Publications, 1975:55-80.

(14.) Brown HM, Su S, Thantrey N. Prick testing for allergens standardized by using a precision needle. Clin Allergy 1981;11:95-8.

(15.) Adinoff AD, Rosloniec DM, McCall LL, Nelson HS. A comparison of six epicutaneous devices in the performance of immediate hypersensitivity skin testing. J Allergy Clin Immunol 1989;84:168-74.

(16.) Kniker WT. Multi-Test skin testing in allergy: A review of published findings. Ann Allergy 1993;71:485-91.

(17.) Krouse HA, Klaustermeyer WB. Immediate hypersensitivity skin testing: A comparison of scratch, prick and intradermal techniques. Immunol Allergy Pract 1980;2:94-101.

(18.) King HC. An Otolaryngologist's Guide to Allergy. New York: Thieme Medical Publishers, 1990.

(19.) Willoughby JW. New concepts in immunotherapy. Otolaryngol Clin North Am 1992;25:71-100.

(20.) Cook PR. In vivo testing and immunotherapy. Current Opinion in Otolaryngology Head and Neck Surgery 1994;2:118-27.