ALLERGY MANAGEMENT FOR THE OTOLARYNGOLOGIST 0030-6665/98 $8.00 + .OO ALLERGY IMMUNOTHERAPY John Fomadley, MD Specific antigen immunotherapy (SIT) ...

1003KB Sizes 4 Downloads 93 Views


0030-6665/98 $8.00

+ .OO


Specific antigen immunotherapy (SIT) is the process of administering increasing doses of an allergen to which the patient has demonstrated sensitivity. The process has been variously referred to as allergy desensitization, hyposensitization, or simply “allergy shots.” This procedure is one of three major categories of accepted therapy for IgEmediated inhalant allergy. The other modalities are environmental control and medical therapy. The purpose of this therapy is to ameliorate the symptoms of inhalant allergy by decreasing the reactivity of the patient to the specific antigen. This clinical intervention has been used empirically for over 80 years, since its introduction by Noon in 1911.18 Although initial treatments were performed based upon clinical success, scholarly works in recent decades have provided double-blinded studies documenting the benefits of immunotherapy. Several mechanisms of action have been suggested for the immunotherapy process, but it remains unclear which pathway exerts the predominant beneficial effect upon the patient. OVERVIEW OF SPECIFIC IMMUNOTHERAPY PRINCIPLES

The observed result of successful specific immunotherapy is a decrease in a patient’s allergic reactivity and symptom relief from IgE mediated allergy. The mechanism by which allergy immunotherapy From the Division of Otolaryngology-Head and Neck Surgery,‘Perm State University College of Medicine, University Hospital, Children’s Hospital, The Milton S. Hershey Medical Center, Hershey, Pennsylvania OTOLARYNGOLOGIC CLINICS OF NORTH AMERICA VOLUME 31 NUMBER 1 * FEBRUARY 1998




achieves this goal has been hypothesized through observation of parameters in the successful, and unsuccessful, immunotherapy patient. Several mechanisms have been proposed as the foundation of successful immunotherapy. Three major theories are espoused: 1. Induction of antigen tolerance by decrease in circulating IgE. Slow increase of antigen in the tissues of patients undergoing SIT inhibits or decreases the formation of specific IgE. Actual decreases in circulating IgE have been observed” 30 after a temporary rise early in immunotherapy. Whether this decrease is due to direct effect upon IgE production or occurs secondary to another effect is not known. It has been suggested that the effect of immunotherapy may be suppression of the T-helper cells or excitation of the T-suppresser lymphocytes in modulating the formation of IgE.8,23 2. Creation of an IgG ‘blocking antibody’. A theory based upon the observed increase in IgG noted in some patients undergoing immunotherapy. This mechanism appears to have attracted interest based upon the reproducible appearance of IgG in successful cases7 14, 25, 26 and the failure to stimulate IgG in immunotherapy failure^.^ Filipp8 has argued that the increased IgG is not related to the clinical improvement but occurs as an ‘innocent immunological epi-phenomenon.’ IgG may at least have a role in the prediction of immunotherapy success. 3. Depletion of inflammatory mediators. The administered immunotherapy may cause a gradual decrease or ’leaking out’ of the mediators of inflammation at a subclinical level. This constant depletion of the contents of mast cells and basophils results in a decreased severity of reaction when inhaled antigen is presented to the cells.8 The efficacy of SIT is dose-dependent. A certain amount of specific antigen must be introduced into the patient to achieve efficacy. This relatively simple concept is made difficult, not only by the varied sensitivities and symptoms of the individual patient, but also because of lack of universal standardization of antigen potency and the use of multiple (confusing) measurement systems. Antigen concentrate vials commonly are labeled as the ratio of antigen weight per volume (w/v). For example, a gram of source antigen extracted in 10 mL of fluid is a 1 : l O w/v preparation. Most commercial antigen vials are shipped at 1:20 w/v, as the 1 : l O extraction fluid is diluted 50:50 with a glycerin stabilizer. This indicator of dilution level is useful not only for the commercial preparations, but also by indicating the subsequent dilution strengths obtained in the office after preparation of testing and treatment vials. A more direct measurement of antigen strength is the protein nitrogen unit (PNU). This measure of nitrogen contained in protein is relatively easy to determine and frequently is cited in current and historic references. Unfortunately, the conversion between measures does not



generalize precisely from antigen to antigen. The conversion varies between 1.5 and 2.5 kg on w/v concentration to each PNU; 2.0 has been used as a general estimate.'O In addition, both aforementioned measures provide only an inexact determination of immunologic activity. A more direct indicator of antigenic activity is the United States allergy unit (AU). The allergy unit is a measure of allergenic activity in humans based upon observed response to intradermal testing. This measure is a valuable tool for extract standardization. Precise knowledge of immunologic activity allows safer transition between vials of antigenically active material. Additionally, exact knowledge of immunologic activity allows a more meaningful comparison of studies between patients and institutions. It is necessary for the current student of allergy to be aware of all of these units of measurement.16 Outcome Measurement Since midcentury, the scientific method has been used to evaluate the efficacy of the empiric immunotherapy. These efforts have yielded objective measures for the evaluation of techniques. Some methods are easily performed in the clinical arena whereas others are practical only for research studies.

1. Sympfom/medication scores: Patients indicate presence of symptoms and level of symptom severity. Medication scores are most valuable when drugs are to be taken on an as needed basis, such as decongestants, expectorants, or certain asthma treatments. The quantity of medications taken serves as an indicator of the level of symptom severity. 2. Nasal air flow or cross section measurements: Rhinomanometry and acoustic rhinometry9,l5 use change in pressure with air flow or acoustic reflection as an indicator of nasal function. Attempts are in progress to improve reproducibility of the determinations. This has been made difficult by the changes of the nasal cycle, and different placements of the measuring devices within the nasal passages. In the case of rhinomanometry, the results are dependent upon patient inspiratory efforts. Although these modalities are not yet sufficiently objective for use in routine patient care, they are a promising research tool. 3. IgG "blocking" antibodies: An observed increase in IgG has been identified with successful immunotherapy. The actual cause-effect relationship of this has been the subject of debate. It appears possible that even if IgG has no effect in mediating hyposensitivity, the elevation of level is an indicator of successful intervention. 4. Nasal provocation measurements: Rather than a measurement tool within itself, this technique is the introduction of standardized quantity of antigen into the nose. Studies can then compare treatments of placebo with respect to nasal cross section, air



flow, release of inflammatory mediators, or symptom scores?,13, 24 Creticos5 used nasal challenge with standardized antigens to demonstrate a decrease in the symptoms of allergic rhinitis as well as a fivefold to tenfold decrease in mediators of inflammation in the noses of subjects undergoing immunotherapy compared to allergic controls. Despite wide varieties in contemporary allergy practice, methods in current use have more similarities than differences. By breaking allergy therapy into component parts, an insight can be gained into current allergy practice in all its major variations. DIAGNOSIS

This step is the identification of IgE-mediated allergy for a given patient. Methods for diagnostic testing are divided into laboratory methods (in vitro) and skin testing (in vivo). In vitro testing is further subdivided, usually by the types of tracer used to identify patientspecific IgE.7 Current skin testing is performed either by prick testing or intradermal titration with varying concentrations of specific antigen.'O Allergy test findings must be correlated with the clinical history and physical examination to confirm the presence of clinical allergy and the appropriateness of treatment. Although similar, initiation of immunotherapy from each type of testing is somewhat different and must be dealt with separately. lmmunotherapy Initiated from Serial Dilution lntradermal Testing

Serial dilution intradermal testing (SDIDT), also referred to as skin end point titration, is discussed as a testing technique elsewhere in this issue. To review, SDIDT uses specific antigen prepared by dilution into a series of decreasing concentrations. The dilution ratio chosen will vary with physician training and preference among the three commonly used methods, l : l O , 1:5, and 1:3. The 1:5 dilution is the technique taught in otolaryngic allergy courses as a safe, standard protocol. This method will be used to illustrate SDIDT. The use of a 1:5 dilution allows determination of patient sensitivity to a specific antigen within narrow tolerances. The mathematics of 1:5 dilutions of a commercially prepared 1:20 concentrate result in relatively unwieldy numbers such as, 1:2500, 1:12,500, 1:62,500, and so forth (Table 1). To avoid dosage error or confusion, each dilution is assigned a number. In this system, diluting a 1:20 concentrate by fivefold obtains a 1:lOO concentration, termed the number 1 dilution. Sequential fivefold dilutions are numbered as illustrated in the table. Beginning with a very dilute mixture (usually #6), a sequence of





Concentrate (commercially prepared) Diluted by five Diluted by five Diluted by five Diluted by five Diluted by five . Diluted by five

1 :20

1:lOO 1:500 1:2500

1:12,500 1:62,500 1:312,500


C 1 2 3 4

5 6

stronger intradermal injections is administered into the skin, creating a wheal. Each wheal is observed for 10 minutes. The definition of the end point is based upon two findings noted on the series of skin wheals: 1. The end point is the first wheal that increases in size by 2 mm within 10 minutes. 2. The next more concentrated dilution creates a wheal that increases by at least an additional 2 mm within 10 minutes. This is termed the confirmatoy wheal.

This end point identifies the patient’s level of sensitivity to the antigen and provides a safe point for the initiation of immunotherapy. As an example, if a patient’s intradermal skin testing progressed as outlined in Table 2, the end point would be dilution number 4, the confirmatory wheal would be that created by dilution number 3, and immunotherapy could begin safely (after a subcutaneous skin test) at the #4 level, a dilution of 1:12,500. Note that the beginning concentration of the immunotherapy is relatively strong, allowing a high quantity of antigen to be safely injected early in the build-up phase. Of equal importance, each antigen is delivered at the highest safe level from the outset. This reduces or eliminates the risk that a particularly high sensitivity antigen will cause a local or systemic reaction during dose advancement. Limiting this reaction would limit the ability to further advance immunotherapy to a level that would provide better treatment for other important but less sensitive antigens. This is diagramatically illustrated in Figure 1. Use of this method does not change the principles of immunotherapy. The benefit provided is the ability to (1) deliver antigen at a Table 2. EXAMPLE INTRADERMAL TITRATION TESTING FOR ENGLISH PLANTAIN Dilution

Wheal Size

#6 #5 #4

5 mm 5 mm 8 rnrn


10 mm



buildup of antigen concentration during irnmunotherapy -------->>

x ***************

antigen a

antigen c antigen d

x *************** x ***************

(not yet therapeutic)

(not yet therapeutic) (not yet therapeutic)

Figure 1. Example of treating antigens of differing sensitivities with the same concentration of antigen. Less sensitive antigens to left, more sensitive antigens to right. Each asterisk represents an irnrnunotherapy injection.

concentration that is safe but closer to the maximum level that the patient will tolerate at the outset; and (2) provide a means to advance each antigen based upon the individual level of sensitivity, to avoid the chance of one antigen limiting progression of the entire series (Fig. 2). In summary, intradermal dilution therapy has the advantage of allowing a semi-quantitative determination of antigen sensitivity. The technique allows differentiation of idiosyncratic responses from true sensitivities. The information permits each antigen to be consistently started at a relatively strong yet safe concentration. The disadvantage is that testing involves an additional number of needle sticks over single needle stick skin prick testing. The increased time and number of injections potentially increase costs for the testing. This additional cost may be considered amortized by elimination of some false positive reactions caused by idiosyncratic reactions during a skin prick test (SPT). Additionally, the course of immunotherapy to the point of symptom relief should be shorter because of the stronger concentration of antigens used at the outset. Appropriate screening and

buildup of antigen concentration during immunotherapy -------->> antigen a antigen b antigen c antigen d

x *************** x *************** x *************** x ***************

Figure 2. lmrnunotherapy when antigens of different sensitivities are started at different concentrations to allow the effective dose to be reached at the same time. The varying antigen sensitivities are accounted for by varying the concentrations where immunotherapy begins. Each asterisk represents an irnmunotherapy injection.



directed follow-up testing based upon history may provide effective information on a patient’s allergies in a cost-effective manner. From a safety standpoint, injection of an antigen into the dermis would be more likely to initiate a reaction than using a SPT. In practice, intradermal injection of antigen using an appropriate technique has been shown to be a safe and reasonable approach. The use of SDIDT has not been identified with a higher risk of serious reaction, either local or systemic, than SPT in clinical use.” The term “skin end point titration” has been the subject of some unfortunate confusion related to the use of this technique as a part of the obsolescent “Rinkel method.’’ In the past, it was believed that the results of progressive intradermal testing could satisfactorily predict the eventual optimum dose for successful maintenance immunotherapy. Despite many advances provided to the field by Dr. Rinkel, his initial belief that the series of test injections could provide an estimate of the true “end point” of therapy proved incorrect. The principles of serial dilution testing and subsequent immunotherapy initiation from this method remain valid and useful. Unfortunately, they have been misidentified as “Rinkel allergy” techniques with resultant confusion as to their efficacy. lmmunotherapy Based Upon Skin Prick Testing

Skin prick testing has been discussed elsewhere in this issue. This method of allergy testing identifies allergic sensitivity by eliciting a skin reaction to the specific antigen. A drop of antigen is placed on the skin and a lancet-type (solid point) needle is used to penetrate the upper layers of the skin. The result is interpreted by the extent of the wheal and flare. Antigens are identified as positive based upon the extent of skin response. Although the response is qualitative, the extent of reaction is used by some practitioners to categorize positive test results into low and high sensitivity responses. This modality should be distinguished from the scratch testing technique. Although the prick test does not reach the depth of intradermal testing, the type of skin opening is deeper and more standardized than the obsolescent scratch test. The shallowness of the scratch and variability of the level of skin penetration severely hampered interpretation of results, and the scratch test is not considered to be of any practical value in current allergy testing9 The benefits of SPT include identification of the allergic response directly from the patient’s skin. This eliminates the possibility of a spurious laboratory result, or lack of sufficient sensitivity and specificity of the given laboratory test. An additional benefit of SPT is the low risk of systemic reaction because of the superficial layer into which the antigen is placed. Disadvantages of SPT include the fact that this test does not determine the precise level of sensitivity for specific antigens. Additionally, there is no opportunity to detect allergic disease at sensitivities below



the concentration of the antigen injected. This may not be a serious drawback. It can be argued that low sensitivity antigens, although potentially important from an environmental standpoint, are not likely to be used in immunotherapy, and therefore the lack of ability to detect these is of small consequence.16 At the conclusion of SPT, the practitioner knows which antigens are positive and which are historically important, but without more than a rough idea of the level of sensitivity to each. There are two options for initiating immunotherapy from this point. The first is to use the SPT as a screening test and proceed with an intradermal or in vitro (laboratory) technique to guide preparation of immunotherapy vials. Alternately, one may proceed directly to immunotherapy from SPT. It is performed by identifying significant antigens with clinical correlation to allergic history, antigen season, and SPT result. The immunotherapy begins at doses sufficiently dilute to minimize the possibility of a systemic reaction. Dilutions of 1 : l O are frequently used in this format but the method will adapt perfectly well to 1:5 dilutions. This method is an acceptable course of therapy for those trained in its use. A reasonable, safe starting dose in this system is an injection of 0.2 to 0.4 PNU. For ragweed that corresponds to 0.1 mL of 1:200,000 w/v extract. This dose is between the number 5 and number 6 dilution used by most otolaryngic allergy practitioners. After a test dose given intradermally, the dose advancement begins. The progressive increase in antigen may be individually tailored to the needs of the patient and/or the experience and preferences of the physician. When a maximum dose (0.5 mL) from the initial vial is reached, the next vial used will contain the next higher dilution to continue antigen build-up. Modification of either the concentration of the different vials or the speed of dosage advancement allows control over the progress of immunotherapy for asthmatic patients, those being injected during a co-seasonal period, or if symptomatic reactions occur. A sample protocol for dosage advancement is shown in Table 3. It can be seen that the problem of not knowing specific antigen sensitivities safely can be circumvented by initiating immunotherapy at a sufficiently dilute level. This is therefore a safe method. The two problems facing the practitioner of immunotherapy from SPT are the length of time required to achieve optimal dosing, and the possibility of obtaining a therapy limiting response from one antigen while others remain far from optimal dosage. Outcome studies are needed to define safety parameters for this and other options in immunotherapy. Concerns about the safety of immunotherapy have been cited as contributing to a dramatic drop in the use of immunotherapy in Europe.1s THERAPY BASED ON IN VlTRO TESTING

In vitro, meaning literally ”in glass,” refers to testing performed outside the patient’s body. It is a generic term, not one that specifies any




W h

Dilution of 1:20 Concentrate

Injection (mL)

First Vial

1 :200,000

1 :10,000

0.1 0.2 0.4 0.8

Second Vial


1 :1,000

0.15 0.3 0.6

Third Vial



0.1 0.15 0.25 0.35 0.5 0.7

Fourth Vial

1 :200


0.1 0.15 0.25 0.35 0.5 0.7

Adapted from Van Metre TE, Adkinson NF: lmrnunotherapy for aeroallergen disease. In Middleton E, Reed CE, Ellis EF, et al: Allergy Principles and Practice, ed 3. St. Louis, Mosby, 1988, p 1336; with permission.

particular testing technique. In vitro allergy testing can involve simple qualitative measures such as dipstick screening techniques. The use of such techniques is limited to allergy screening and to assisting in guiding the medical and environmental aspects of allergic disease. Dipstick-type screening tests do not provide sufficient information for the initiation of allergy immunotherapy. The in vitro tests that allow therapeutic decisions and the initiation of immunotherapy are variations of the "sandwich type immunoassay. In these studies, specific IgE antibody is identified by allowing it to bind with known antigen. The specific IgE antibody then acts as an antigen for an "anti-human" IgE molecule that has been tagged previously with a tracer material. Identifying tracers may be based on a variety of principles including fluorescence, radioactivity, and chemiluminescence. Antibody assays using radioactive labels are termed radioallergosorbent tests, or "RAST" tests. The RAST tests, particularly ,the modified RAST, has been considered a standard against which other immunoassays are judged. RAST testing was developed in the 1960s and was used clinically with some success in the 1970s. Early tests suffered from high levels of background radioactive degradation causing the test to miss an unacceptable number of truly allergic patients (low sensitivity). A different



problem was the lack of easy correlation between the results of RAST testing with skin testing results for a given patient. Further development yielded the modified RAST, a system that lowered background radioactivity, improved sensitivity, and changed the reporting system to more closely conform to results reported using intradermal dilution therapy. The modified RAST yields a reading of 0 (non-allergic), 0/1 (equivocal), or allergy class 1 through 6, with larger numbers indicating higher concentrations of specific IgE, and therefore greater sensitivity to a given antigen. A modified RAST result of a class 4 allergy to June grass is designed to correlate to an end point of 4 using SDIDT. This means that in vitro technology can reproduce information about levels of specific antigen sensitivity without risk of systemic reactions, flash responses, or patient’s ability to cooperate with the repeated pricks or injections necessary to complete skin testing. In practice, it is clear that many factors can alter skin reactivity. Some safeguards are required to ensure safety of patients undergoing therapy based upon in vitro testing. 1. Correlate skin testing and in vitro determinations. The most straightforward method of correlating skin testing and in vitro determinations is to periodically obtain an in vitro test at the same time that skin testing is performed. Obviously, patients must not be double-billed for these tests; rather, it should be considered a normal quality control practice expense. Unpredictable or widely varying results may point to problems with either the in vitro or the skin testing technique, or may relate to the potency of antigen used in the office determinations. A steady variance such as an uniform shift of end points in one direction or the other that is predictable is a quite acceptable situation. This variation is noted and in vitro results are appropriately adjusted before interpretation. The skin test results are always considered the “true” standard as these are the determinations achieved from actual patient skin response. 2. Shifting the end points: using RAST-1 and RAST-2. Moving the in vitro end points to one dilution less concentrated before preparing immunotherapy vials provides an additional margin of safety. This shift of end points across the spectrum of an individual patient‘s in vitro results is termed ”treating at RAST-1.” The technique provides a margin of safety while still initiating immunotherapy at a level individualized to the patient’s sensitivity to the specific antigen. Table 4 demonstrates a modified RAST test result with the second column showing a RAST-1. Note that the ”minus” does not indicate an arithmetic minus, but is an indication that move dilution step has been selected. The name may be confusing but is deeply rooted in the literature at this point. With particularly “brittle” patients such as asthmatics, patients who have evidence of severe reactions in the past, or at times when therapy has begun co-seasonally, alteration of the end



point to RAST-2, or 2 end points less concentrated provides an additional margin of safety. More importantly, the relative levels of sensitivity between antigens is preserved. In vitro testing results must still be confirmed by skin testing before initiating immunotherap y. 3. Observe all CLIA regulations. The Clinical Laboratory Improvement Act of 1988 (CLIA ’88) has received criticism for its cost and the requirement levels imposed upon the physician’s office laboratory. Nevertheless, the act has provided regulatory authority to assure that all laboratories function under identical govemmental ,criteria. This additional level of quality assurance has in fact become a medicolegal requirement. Whether the CLIA regulations are applied to an individual physician’s laboratory or to a commercial operation, the credentials of those operating the laboratory and the ability to detect the accuracy of unknown sample tests has provided an important safeguard to the reproducibility and accuracy of laboratory testing. 4. Skin test all patients before initiation of therapy. It is recognized that variability can exist in a patient’s skin responsiveness based upon seasonal or even some daily fluctuations. Therefore, slight variation from in vitro to skin testing also is possible. In all cases, the final determination of patient safety is achieved by testing the patient with a subcutaneous injection of the prepared vial prior to initiation of immunotherapy. PREPARATION OF TREATMENT VIALS

Not all positive antigen responses require inclusion in immunotherapy. Antigens should be considered based upon patient history to assure that they are significant to the patient’s overall care plan. Furthermore, many antigens cross react. This is the explanation for multiple responses within a given family group of antigens. A patient may have a class 5 response to June grass, with lesser levels of positive reactions to grasses such as timothy, that may not even be located in the patient’s environment. Recognition of cross reactivity is important to successful allergy therapy. The cross reacting antigens do not represent a true environmen-



End Point

Ragweed English plantain Timothy Bermuda grass



3 5 3

4 6





tal allergy, and adding them effects an unintended increase in the antigen presented during immunotherapy, and may result in an increased risk of local or systemic reactions as immunotherapy advances to higher doses. Deciding what antigens should be placed into vials requires a suitable allergy education background and experience. Once decisions are made with respect to need for immunotherapy and appropriate antigens to include, the treatment vials are prepared. If an end point has been identified by SDIDT or in vitro determinations, this level defines the safe starting concentration. It would be correct (but not practical) to inject a patient with the actual end point dose of each antigen. In the example provided in Table 5, this would require injections starting with 0.1 mL of #3 dilution ragweed, 0.1 mL of #4 timothy, and so forth. A more practical solution is to mix a number of antigens into one vial at the correct antigen concentration. By using a more concentrated dilution of each antigen, the various antigens can be mixed into a multi-dose vial containing the correct concentration for each of the antigens. An effective algorithm for mixing a ten-dose maintenance vial is illustrated in Table 5. Recall that in a 1:5 dilution system, 0.5 mL of the end point dilution equals 0.1 mL of one dilution more concentrated, and also equals 0.02 mL of two dilutions higher. Use of the more concentrated dilution will therefore provide the same number of molecules of antigen (or, to use other units, PNU) in less fluid, allowing room for additional antigens in the mixture. Antigens may be separated by high and low sensitivities; some practitioners prefer to separate out molds or other antigens presumed to be potential ’troublemakers’ in a given patient, to facilitate identification of the offending antigen if a local reaction should occur. If the immunotherapy is to be based upon SPT, antigens appropriate for inclusion in therapy are divided into high and low sensitivity groups based primarily upon the reaction observed during prick testing. All “low sensitivity” antigens are mixed at an identical concentration, usually 1:20,000 w/v. Selected “high sensitivity” antigens are then mixed into a separate vial at a concentration of 1:200,000 w/v. A skin test is Table 5. ALGORITHM FOR MIXING A 10-DOSE MAINTENANCE VIAL Antigen

End Point



Ragweed English plantain Timothy Bermuda

3 4 4 5

.02 mL .02 mL .02mL .02mL

#1 #2 #2 #3

Subtotal-quantityof antigen Add diluent to total of 5 mL

Yields Total x10= 0.2 mL #1

x 10= 0.2 mL #2 x10= 0.2 mL #2 x10= 0.2 mL #3 0.8 mL 4.2 mL 5.0 mL vial



placed with .05 mL injected intradermally to test the serum initially for reaction before progressing with a gradual regimen of shot therapy. The actual time between shots and the amount of antigen increase from injection to injection may vary with physician preference. DOSAGE ADVANCEMENT

The methods of dose advancement depend more upon patient factors than the format of testing used. So-called ‘conventional schedules’ for inhalent allergens begin with an intradermal test dose of 0.05 to 0.1 mL. Following this, otolaryngic allergy dosage schedules often proceed on a weekly basis with an increase of 0.05 to 1.0 mL each week. After reaching 0.5 mL, the concentration injected is now equivalent to 0.1 mL of the next higher dilution (again using 1:5 as an example) and dosage escalation continues to the point of symptom relief.I4 The 1 : l O dilutions favored by the medical allergy community progress from initial skin test to 0.1 mL of the 1:20,000 w/v extract and advances in similar fashion on a weekly or twice weekly basis to a symptom-relieving dose of approximately 0.5 mL of a 1:200 w/v extract (see Table 3).20 RUSH IMMUNOTHERAPY

The biggest drawback to immunotherapy from a practical standpoint is the length of time required to complete a safe dose escalation. Faster advancement, termed “ r u s h therapy, has been attempted at various times through the years. These protocols have been associated with an increased incidence of reactions. The trade-off between slow advancement or increased side effects has been the subject of continued study. Rush immunotherapy studies the ability to provide therapy in a considerably decreased time period, such as 2 to 5 days. Hejjaoui et a1 described a series of 290 patients hyposensitized over 3 days, but with 36% of patients developing systemic reactions.’l Premedication before rush injection protocols decreased the incidence of severe reaction to under l6%, with a per injection reaction rate between 3% to 7%.11, It appears that rush therapy methods, even with aggressive premedication, will not achieve a safety profile acceptable to physicians and patients for generalized use with current antigen preparati0ns.l.l8 Safer, accelerated allergy therapy may require a modification of the methods by which antigens are extracted and presented to the immune system. Alum-extraction techniques provide for a slow release of antigen that may decrease the number of shots needed, and the risk of generalized reaction per shot. This method is currently limited by the vigorous l2rZ2



extraction technique required that denatures many antigens, destroying their immunogenicity.


It is hoped that standardization of antigen will allow calculation of precise optimum doses in the future. Present maintenance therapy is titrated by differerit practitioners to an optimal dose of either symptom relief or maximally tolerated dosage. The quantity of injection required for successful immunotherapy was initially an empiric determination. It was observed that response improved with increasing antigen dosage, but also that rapid increase in injection quantity was accompanied by increased adverse reactions. Efforts were directed to slowly increase the quantity of antigen injected to the highest level that could be tolerated by the patient. Not surprisingly, this "maximally tolerated dose" provides control of symptoms, but with an increased level of adverse reactions.'O Another format for dosing of immunotherapy is to advance the quantity of antigen injected until the patient's symptoms are resolved. This has been termed "optimum dose immunotherapy," or perhaps more modestly, the "dose of symptom relief." Further advancement is withheld, presumably at a level where the risk of adverse reaction is considerably less. In the context of clinical practice, both methods have merit. A perennial antigen that is controlled with a given level of immunotherapy needs no further advancement of dosage, as symptom improvement has been achieved. On the contrary, a seasonal antigen such as ragweed would be expected to produce little or no symptoms outside of the season, and therefore, it is not possible to titrate immunotherapy dosage to symptom relief except during the co-seasonal months. It is for all practical purposes therapy geared to the maximally tolerated dose. Improvement in the area of appropriate maintenance dosages is to be expected as standardization of antigen studies of levels of antigen required for maximal safe relief continues. Ragweed has been studied, demonstrating that doses less than 10 AU are ineffective and those greater than 1000 AU create an excess number of systemic reactions.27


Two key issues related to the administration of immunotherapy are the indications for therapy and the locations acceptable for delivery of shots. Debate remains active (and definitive data lacking) on the topic of where immunotherapy can be safely administered. In particular, the removal of a patient from the allergy office to the primary care provider



raises issues of managed care, responsibility for outcomes, and overall safety. Home immunotherapy once antigen doses have reached stable maintenance levels is convenient and may be found to be safe under certain circumstances. Safety Concerns

To minimize risk and improve efficacy, it has been recommended that SIT be prescribed by specially trained physician practitioners, and administered under the supervision of physicians trained to manage systemic reactions and with the immediate availability of epinephrine should anaphylaxis occur. In the United States, controversy continues on various topics. Administration of shots outside the medical office environment has provoked debate. Can immunotherapy be given at home during build-up, during maintenance, or not at all? Another concern relates to the length of the period following an allergy injection when a patient must remain in the office for observation. Twenty minutes has been suggested as an appropriate interval. Definitive data are lacking.16 Asthmatic patients also create a clinical dilemma. Those with allergic disease contributing to bronchospasm can derive benefit from immunotherapy by decreased asthmatic response to antigenic challenge, but these patients have been noted to suffer a disproportionately greater number of severe reactions to the injection therapy. CESSATION OF THERAPY

It is unclear how long patients require immunotherapy to achieve maximum benefit, and whether hyposensitization conferred is a lifelong benefit. Particular questions relate to whether or not immunotherapy should be modified or stopped at 1 year if no improvement is seen, and whether 5 years is a reasonable length of time for immunotherapy to attain a maximal effect. With patients who attain systemic relief with immunotherapy, practitioners may take the patient off shots after 5 years to ascertain whether immunotherapy has conferred a long-lasting allergy tolerance. Controversy in Allergy Therapy

Given the subjective nature of most allergy complaints and the fact that the subcellular immunology of SIT awaits a more complete evaluation, it is natural that different philosophies, or styles of therapy, would emerge. Even the place of immunotherapy in the care of the allergy patient remains a matter of some debate. Some authors have suggested immunotherapy be reserved for failures of avoidance and pharmacotherapy measures, although others have recommended its use as a means of



freeing patients from a lifetime of environmental and medication needs. In a manner roughly analogous to the way the disciplines of general surgery and gastroenterology “share” the study of the digestive tract, medical allergists and otolaryngologic allergists have developed different but similar approaches to the sinonasal tract. This factor has undoubtedly had both favorable and unfortunate effects on the discipline. Due in large part to these differences, rarely are fair and uniform comparisons among the allergy therapy techniques available. This review was based where possible upon areas of reasonable agreement and common ground in the literature. Where controversy exists, an attempt has been made to review the literature support for varying viewpoints as fairly as possible. References 1. Bousquet J, Guerin B, Dotte A, et al: Comparison between rush immunotherapy and an alum adjuved pyridine extracted material in grass pollen allergy. Clinical Allergy 15:179-193, 1985 2. Clement PA, Hirsch C: Rhinometry-A review. ORL J Otorhinolaryngol Relat Spec 46173-191,1984 3. Cole P: Rhinomanometry 1988: Practice and trends (review). Laryngoscope 99:311-15, 1989 4. Creticos PS: Immunotherapy with allergens. JAMA 268(20):2834-2839, 1992 5. Creticos PS, Adkinson NF Jr, Kagey-Sobotka A, et al: Nasal challenge with ragweed pollen in hay fever patients. J Clin Invest 762247-2253,1985 6. Creticos PS, Marsh DG, Proud D, et al: Responses to ragweed-pollen nasal challenge before and after immunotherapy. J Allergy Clin Immunol 88661-674, 1991 7. Durham SR, Kay AB, Hamid Q: Changes in allergic inflammation associated with successful immunotherapy. Int Arch Allergy Immunol 107282-284, 1995 8. Filipp G: Specific desensitization and its mechanisms. Allergol Immunopathol (MADR) 10305-318, 1982 9. Fireman F: Nasal provocation testing: An objective assessment for nasal and eustachian tube obstruction. J Allergy Clin Immunol81:953-960, 1988 10. Fornadley JA, Corey JP, Osguthorpe JD, et al: Allergic rhinitis: Clinical practice guideline. Otolaryngol Head Neck Surg 115115-122, 1996 11. Gordon BR Allergy skin tests and immunotherapy: Comparison of methods in common use. Ear Nose Throat J 69:47-62, 1990 12. Hejjaoui A, Dhivert H, Michel FB, et al: Immunotherapy with a standardized Dermatophagoides pteronyssinus extract. IV. Systemic reactions according to the immunotherapy schedule. J Allergy Clin Immunol85:473-9, 1990 13. Hejjaoui A, Ferrando R, Dhivert H, et al: Systemic reactions occurring during immunotherapy with standardized pollen extracts. J Allergy Clin Immunol89:925932, 1992 14. Kesvanathan J, Swift DL, Fitzgerald TK, et a 1 Evaluation of acoustic rhinometry and posterior rhinomanometry as tools for inhalation challenge studies. J Toxic01 Environ Health 48295307, 1996 15. King HC: An Otolaryngologists Guide to Allergy. New York, Thieme Publishers, 1990 16. Lund VJ: Objective assessment of nasal obstruction (review). Otolaryngol Clinks of North America 22:279-290, 1989 17. Middleton E, Reed CE, Ellis EF, et a1 Allergy Principles and Practice, ed 4. St. Louis, Mosby, 1993, pp 1497-1499 18. Noon L Prophylactic inoculation against hay fever. Lancet 1:1572, 1911 19. Norman PS: Immunotherapy-State of the art. Allergy Procedures 6:249-254, 1985 20. Ohman JL: Allergen immunotherapy review of efficacy and current practice. Clinical Allergy in the Medical Clinics of North America 4977-991, 1992



21. Parker AJ, Clarke PM, Dawes PJ, et al: A comparison of active anterior rhinomanometry and nosometry in the objective measurement of nasal obstruction. Rhinology 28:47-53, 1990 22. Portnoy J, Bagstad K, Kanarek H, et a1 Premedication reduces the incidence of systemic reactions during inhalant rush immunotherapy with mixtures of allergenic extracts. Ann Allergy 73409-418, 1994 23. Rocklin RE, Sheffer AL, Greineder DK, et al: Generation of antigen-specific suppresser cells during allergy desensitization. N Engl J Med 302:121s1219, 1980 24. Roithmann R, Cole P, Chapnik J, et al: Acoustic rhinometry in the evaluation of nasal obstruction. Laryngoscope 105275-281, 1995 25. Sadan N, Phyne MB, Mellits ED, et a1 Immunotherapy for pollinosis in children: investigation of the immunologic basis of clinical improvement. N Engl J Med 2 8 0 6 2 s 627, 1969 26. Scadding GK, Darby YC, Austin CE: Acoustic rhinometry compared with anterior rhinomanometry in the assessment of the response to nasal allergy challenge. Clin Otolaryngol 19:451-454, 1994 27. Sobotka AK, Valentine MD, Ishizaka K, et a1 Measurement of IgG blocking antibody: Development and application of a radioimmunoassay. J Immunol 11784-90, 1976 28. Turkeltaub PC: The importance of allergen dose on the safety and efficacy of immunotherapy of ragweed hay fever with standardized short ragweed extracts. J Allergy Clin Immunol77211, 1986 29. Van Metre TE, Adkinson NF, Amodio FJ, et al: A comparison of immunotherapy schedules for injection treatment of ragweed pollen hay fever. J Allergy Clin Immunol 69:181, 1982 30. Zeiss CR, Metzger WJ, Levitz D Quantitative relationship between IgE immunotherapy with ragweed antigen in patients given immunotherapy with ragweed antigen E. IINUO I~ 28250-255,1977 Clin EXP R

Address reprint requests to John Fomadley, MD Associate Professor Division of Otolaryngology-Head and Neck Surgery Penn State College of Medicine University Hospital, Children’s Hospital The Milton S. Hershey Medical Center 500 University Drive PO Box 850 Hershey, PA 17033-0850