9

Immunotherapy Based on Quantitative Testing

Antigen treatment vials have been prepared. This chapter gives a map for the initiation, escalation, maintenance, and discontinuance of immunotherapy. The approach is basic and very conservative, with safety in mind. Modifications from this protocol, expanded commentary on the subject matter presented, and complementary information on other forms of immunotherapy are beyond the scope of this chapter, yet may be found elsewhere.2,3 Repetition and redundancy have been incorporated at times to reinforce important information. Treatment begins with the vial test.

♦ The Vial Test

The initiation of immunotherapy, administration of a starting dose and a subsequent dose escalation sequence should not take place without the successful completion of a vial test for each vial in the treatment set. This is a safety and quality control measure. The vial test is a bioassay, an intradermal skin test performed on the patient using the mixture of antigens in the treatment vials of that specific patient, the content of which is based on the patient’s responses to quantitative testing of those antigens. The vial test result must fall within a range previously observed to correlate with the likelihood of a safe response to the initial treatment dose. In the case of in vitro-based immunotherapy, the vial test is the only bioassay that is performed in the process of testing and initiation of treatment. An appropriate response to a vial test is mandatory before initiating in vitro–based immunotherapy. Although IDT and MQT have evolved from methodologies that infer safety in the initiation of subsequent immunotherapy, the added bioassay of the vial test as a safety measure is still advocated in these situations.

The vial test is performed as follows. A 4-mm intradermal wheal is raised using a small volume of antigen (usually 0.01 mL) from the treatment vial being tested. Remember to apply both positive (histamine) and negative (diluent) controls at the same time. The technique is described elsewhere.2–4,7 After 10 minutes, the size of the vial test wheal is measured. A wheal diameter of 13 mm or less is a passing (acceptable) response. A first immunotherapeutic injection from this vial is now predictably safe. That being said, any time a treatment injection is given, the materials, equipment, and expertise for treating adverse reactions, including anaphylaxis, should be in place, and the patient should be observed for an appropriate amount of time as described elsewhere.^5,6 Most authorities consider the antigen quantity applied during an acceptable vial test (producing a wheal of 12 or 13 mm) to constitute the first dose in the treatment escalation scheme. Others would allow an additional 0.05 mL of antigen to be given subcutaneously (SC) on the vial testing day if the vial test result is 11 mm or less.^2,3 I prefer the more conservative approach, especially for novice clinicians, of simply commencing treatment with 0.05 mL of the treatment vial 5 to 7 days after the vial test is administered.

What if the result of the vial test is unacceptable? If the resultant wheal is greater than 13 mm in diameter, a satisfactory margin of safety cannot be predicted based on the antigen vial as it has been prepared. When the initial vial test result is greater than 13 mm, one may simply repeat the test 48 to 72 hours later. If the initial unacceptable test is due to a timelimited, concomitant, or synergistic effect of inhalant allergen, food sensitivity, chemical sensitivity, technical error in doing the vial test, or associated physical or disease-related condition(s), the repeat test may be acceptable and commencement of immunotherapy is predictably safe. This situation has been compared with the “flash response” in abnormal IDT whealing patterns described elsewhere.^7,8 If the wheal resulting from the repeat test is still greater than 13 mm in diameter, the patient should be tested with a fivefold weaker dilution, and successive fivefold weaker dilutions of the treatment vial if necessary, until an acceptable result (13 mm or less) is found. This IDT-like approach has been called titrating the vial. I believe the subsequent weaker test(s) should be done up to 96 hours after each preceding test(s) to minimize possible adverse effects due to antigen loading. If the problem with the initial vial test is one of antigen potentiation due to an additive effect on potency in the antigen mix (synergy), an acceptable fivefold dilutional mix of the initial vial should be found and therapy can then commence with a predictable safety. If this does not produce an acceptable result, or if at any time there is a question of the accuracy in the mixing of the initial treatment vial, the in vitro or in vivo diagnostic testing results should be reviewed. The vial should be mixed again, and, for the sake of safety, the vial test performed at a fivefold weaker dilution.

If the above algorithm fails to produce an acceptable result, the patient should be retested for each individual antigen. The safest and most definitiveway to do this is to repeat the diagnostic testing for each antigen in the vial using IDT. This automatically overcomes any differences between IDT and MQT for exact determination of endpoint, and it will show any disparity between m-RAST/ImmunoCap and their correlation with skin endpoint. Alternatively, if the initial antigen evaluation was by means of an in vitro quantitative test, repeating the in vitro test may reveal a different result (perhaps a seasonal variation) and lead to a revised antigen mix in the treatment vial. If not, then IDT should be performed as noted above. Mabry9 describes a similar approach called incremental vial testing, which is less time- and resource-intensive for evaluation of endpoints via IDT. This process involves educated extrapolations from the initial endpoints. This may save some testing of the progressing dilutions leading to an endpoint. The relevance and accuracy of the method’s results still must be shown with the subsequent vial test of the new treatment vial. I refer the more experienced clinician to the cited references for a more complete description.^2,9 No matter what method is used to arrive at a new treatment vial, a vial test result must be acceptable before treatment is started.

Lastly, if an urticarial or systemic response occurs with a vial test, a review is necessary of the patient, the history, the diagnostic antigen testing, the mixing and administration, indeed the whole path of diagnosis leading to treatment. Even after correction of any problem(s) and subsequent acceptable results on a vial test, the indication and decision for pursuing immunotherapy should be reconsidered.

♦ Initial Dosing

At this point, all of the patient’s treatment vials have produced acceptable vial test results (i.e., 13 mm or smaller wheal). A conservative 5 to 7 days have passed and it is now time to give the initial dose from each vial. When giving any immunotherapy injection, the patient should not be acutely ill or unstable in any way. Vigorous exercise the day of the injection( s) should not be permitted, either pre- or postinjection(s), as this may increase the risk of adverse reaction. The blood pressure should be acceptable and asthmatics should not be in any distress or below their usual forced expiratory volume in 1 second (FEV₁). The initial dose is 0.05 mL SC of extract from each treatment vial(s), at separate sites if more than one vial is used. Injections are usually made in the posterior portion of the arm(s) over the triceps. If an injection is mistakenly given intramuscularly (IM) rather than SC, the result will be pain and most likely a locally symptomatic induration. The patient should remain in the office to be monitored for 20 to 30 minute after the injection(s). Having patients wait in an area where their activity can be observed, a place in which the nurse can talk with them as necessary, is advisable. When adverse reactions occur, the shorter the time interval between the injection( s) and the onset of symptoms, the greater is the tendency for severity of the reaction. Although some authorities have advocated up to 1 to 2 hours observation, 20 minutes has been shown to be usually adequate and is the currently recommended minimum.2 If the patient was initially tested with IDT, the amount of antigen given during the testing to produce an endpoint wheal and a subsequent confirming wheal is greater in volume and total concentration of antigen than the 0.05 mL given as the initial treatment dose. This adds another layer of safety in addition to the vial test. Before the patient leaves the office, the nurse should check the size of any local swelling, and note the production of any local reaction or symptoms, to help confirm the appropriateness and safety of the dosing. The patient should be instructed to report any subsequent adverse symptoms, and if need be, to seek emergent help in the rare case of a severe, delayed response. Even if the patient makes no such reports, an inquiry at the time of the next visit should be standard practice.

In the initial escalation scheme, injection sessions subsequent to the initial dosing occur once or twice a week (at least 3 to 4 days apart). In the manner and setting noted above, the subsequent doses are conservatively increased by 0.05 mL per vial, per session, until a dose of 0.50 mL SC per vial is attained. Typically, escalation occurs in this fashion: 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50 mL (Table 9-1).¹ This is a conservative initial escalation scheme that may be used by veteran and novice clinicians alike, ensuring a high standard of safety. With experience, in a nonbrittle, low-reacting, nonasthmatic patient, not in any high sensitivity season, and after all due consideration, a more rapid escalation schedule might be chosen in the initial escalation scheme only. Such a scheme could proceed thusly: 0.05, 0.10, 0.20, 0.30, 0.40, 0.45, 0.50 mL.

Rush immunotherapy is a term applied to a protocol of rapid desensitization over a short period of time, ranging fromhours to days depending on the protocol. These methods involve techniques and immunotherapy sequences different from those described in this book.3 Safety should always be the first priority of the clinician. Any type of rapid or rush escalation scheme saves time and materials, but at the expense of increased risk, which must be acceptable before proceeding.

From Ward WA. Immunotherapy dosage based on skin endpoint titration. In: Mabry RL, ed. Skin Endpoint Titration. New York: Thieme, 1992:40, with permission.¹

Some definitions are needed to clarify the direction and expected outcomes of further escalation beyond the initial series of doses. A symptom-relieving dose is a dose that generally relieves the allergic symptoms for a period of a week. The maximally tolerated dose is a known or predicted dose at which further escalation will produce a significant adverse reaction. The optimal treatment dose is a dose that approaches the maximally tolerated dose, is a conservative ideal for maintaining potent immunotherapy, and usually does not have to be changed with fluctuations in patient sensitivity. This optimal treatment dose usually relieves symptoms while producing a local reaction that is no more than 25 to 30 mm in diameter, not present for more than 24 to 48 hours, and is not associated with other local or systemic symptoms. A dose causing a 30-mm local reaction indicates that further advancement at that time may produce adverse reactions. This may signal a maximally tolerated dose.

The maintenance dose is the dose required for the remainder of the course of immunotherapy to elicit the favorably preserved, immune response for desensitization. This dose (often the optimal dose) is usually beyond the symptom-relieving dose and less than or equal to the maximally tolerated dose. Conservative maintenance immunotherapy uses an optimal treatment dose, whereas more aggressive therapy pushes the maximally tolerated dose. I prefer the optimal treatment dose as a maintenance dose, if possible, as it provides a greater margin of safety with less need for periodic up- or downregulation.3 The goal of dose escalation is to establish a true maintenance dose of sufficient antigenic volume and concentration to allow, over a period of time, for the immune changes necessary to effect a prolonged state of desensitization and symptom relief or maximal improvement. Usually this requires the vast majority of the antigen concentrations used in the vials to eventually, and safely, to be mixed from concentrations of dilution No. 1 or concentrates, with an injection interval span of 2 to 3 weeks, and over an average therapy span of 3 to 5 years.^2,3 Symptom relief is always the goal, but in reality, chronic “allergic” rhinitis is not always purely allergic in origin. Therefore, there are situations when nonallergic stimuli will continue to produce less than total relief outcomes. Examples would be of the allergic patient who cannot totally avoid cigarette smoke, or the patient with recalcitrant vasomotor (idiopathic) triggers. Without these exposures or triggers, the patient may have total relief of his/her allergic symptoms with appropriately maintained immunotherapy, but with them, may be only improved. It is possible, although unusual, for the patient to reach a maximally tolerated dose at the end of the escalation of the initial vial. If this occurs, the clinician should reevaluate the diagnosis-to-management pathway, and seek an explanation of this occurrence.

♦ Subsequent Escalation

Having successfully completed the initial escalation scheme with the patient tolerating 0.50 mL SC from the initial treatment vial(s), dose escalation is now continued by mixing treatment vial(s) No. 2 with the same antigens, fivefold stronger than the concentrations used in the first, or initial, treatment vial(s). For example, if dilution No. 2 of antigen A was used in mixing the initial treatment vial, dilution No. 1 of antigen A would be used in mixing treatment vial No. 2. Adding the diluent would be the same as before, and as described elsewhere. Mathematically and pharmacologically, because fivefold dilutions are involved, 0.10 mL of vial No. 2 is the same concentration (only in a different volume) as 0.50 mL of vial No. 1, the initial treatment vial. Therefore, the patient who tolerated 0.5 mL of the initial vial will receive the same amount of antigen in 0.10 mL of the next vial, vial No. 2. However, it is strongly recommended that continuing therapy from vial No. 2 should be preceded by a vial test, and that the test should be initiated in the allergist’s office, even if the patient normally gets his/her injections at another physician’s office or is on home immunotherapy. Realize that a vial test wheal >13 mm, with no local or systemic symptoms, could result for any of the possible reasons previously reviewed, or be due to the higher concentrations of antigen and glycerin in vial No. 2. After safety concerns have been satisfied, the clinician may cautiously continue escalation by starting with an injection of 0.05 mL from vial No. 2. Starting with 0.05 mL from vial No. 2 rather than 0.10 mL is another safety measure against potential changes of reactivity in the fivefold, up-concentrated vial No. 2, which is fresher than the preceding vial and could conceivably be slightly more antigenic. The dosing is escalated by 0.05 mL per injection session as described before: 0.05, 0.10, 0.15, 0.20, 0.25, 0.30, 0.35, 0.40, 0.45, 0.50 mL.

A local, subcutaneous induration or swelling of 25 mm at the injection site, without any urticaria or systemic symptoms, resolving in 24 to 48 hours, is generally an indication that the maintenance dose for that vial is near. The dose producing such a response may be an optimal treatment dose. A response of 30 mmis an indicator that further escalation may produce an adverse reaction. This probably represents a maximally tolerated dose. Any dose that produces urticaria or a systemic reaction is a nontolerated dose and presents a red flag indicating a need to stop escalation. Always reevaluate the diagnosis-to-management process when a systemic reaction has occurred. The dosage should be reduced to one producing no more than a 25-mm transient swelling and no urticaria or systemic symptoms. The safest way to do this is to vial test the patient again with a new, remixed, error-corrected vial producing an acceptable result with no systemic symptoms or urticaria. Then start escalation at a dose of 0.05 mL SC.

Once a patient has safely continued to have good results from injections at 2- to 3-week intervals, and has been on therapy for 3 to 5 years, consideration may be given to discontinuing immunotherapy. This is usually done after the patient’s historically most significant season has passed with no significant problems. If symptoms return within 2 months of stopping the injections, the patient may be vial tested from the most recent vial(s), and if the result is acceptable, therapy may be restarted at a lower dose (usually the previous maintenance dose). The most conservative approach would be to restart escalation at 0.05 mL per vial(s) from the vial giving the acceptable vial test. If the current vial(s) has expired, and the season has not changed, then a new vial(s) must be made, and a vial test(s) performed. If the vial test is unacceptable, then the algorithm described earlier should be followed. Longer periods between cessation of therapy and resumption require retesting, and perhaps starting the desensitization process over again.

1. Ward WA. Immunotherapy dosage based on skin endpoint titration. In: Mabry RL, ed. Skin Endpoint Titration. AAOA Monograph Series. New York: Thieme, 1992

2. Vial preparation and immunotherapy. In: King HC, Mabry RL, Mabry CS, Gordon BR, Marple BF, eds. Allergy in ENT Practice: The Basic Guide, 2nd ed. New York: Thieme, 2005

3. Haydon RC, Gordon BR. Aeroallergen immunotherapy. In: Krouse JH, Chadwick SJ, Gordon BR, Derebery MJ, eds. Allergy and Immunology—An Otolaryngic Approach. Philadelphia: Lippincott Williams & Wilkins, 2002

4. Blending skin testing and in vitro testing in clinical practice. In: King HC, Mabry RL, Mabry CS, Gordon BR, Marple BF, eds. Allergy in ENT Practice: The Basic Guide, 2nd ed. New York: Thieme, 2005

5. Gordon BR. Anaphylaxis: prevention and treatment. In: Krouse JH, Chadwick SJ, Gordon BR, Derebery MJ, eds. Allergy and Immunology—An Otolaryngic Approach. Philadelphia: Lippincott Williams & Wilkins, 2002

6. Allergic emergencies. In: King HC, Mabry RL, Mabry CS, Gordon BR, Marple BF, eds. Allergy in ENT Practice: The Basic Guide, 2nd ed. New York: Thieme, 2005

7. Testing methods for inhalant allergy. In: King HC, Mabry RL, Mabry CS, Gordon BR, Marple BF, eds. Allergy in ENT Practice: The Basic Guide, 2nd ed. New York: Thieme, 2005

8. Fornadley JA. Skin testing in the diagnosis of inhalant allergy. In: Krouse JH, Chadwick SJ, Gordon BR, Derebery MJ, eds. Allergy and Immunology—An Otolaryngic Approach. Philadelphia: Lippincott Williams & Wilkins, 2002

9. Mabry RL. Blending skin endpoint titration and in vitro methods in clinical practice. Otolaryngol Clin North Am 1992;25:61–70