2.2.1 Percutaneous Skin Testing

Dose

Unless an individual is suspected to be at greater risk for anaphylaxis, the initial starting dose is 1 drop (approximately 0.05 mL) of undiluted allergenic extract.  For individuals suspected to be at greater risk for anaphylaxis (for example, as indicated by a history of allergen-induced anaphylaxis), initiate percutaneous testing with a sequence of serial 10-fold dilutions of undiluted allergenic extract spaced 15‑20 minutes apart [see Preparation for Administration (2.1)].

Administration

• Percutaneous Test:  Place one drop (approximately 0.05 mL) of allergen on the skin and pierce through drop superficially into the skin, lifting slightly.  Use a skin test device, such as a sterile needle, lancet, or bifurcated needle.
• Percutaneous Test using self-loading devices:  Refer to the manufacturer’s product instructions.

Concurrently, use a positive histamine skin test control to identify patients whose recent use of drugs with antihistamine activity may result in a false negative skin test.  Apply a 50% glycerin solution as a negative control, to identify false positive responses to the extracting fluid used in the manufacture of allergenic extracts, or due to dermographism [see Drug Interactions (7)].

Interpreting Results

For interpretation of percutaneous skin tests, refer to the information provided in Allergy Diagnostic Testing:  An Updated Practice Parameter.1  In addition, follow the directions provided with the percutaneous skin test devices.  Measure wheal responses for the histamine positive control test at 15 minutes and for the allergen tests at 15 to 20 minutes.

• The negative control (50% glycerin solution) response should measure < 3 mm wheal and ≤ 10 mm flare.1
• Response to positive controls should be at least 3 millimeters larger than the response to the negative control.
• If either the response to the histamine positive control or to the negative control do not meet the criteria above for acceptable wheal size, the results for the allergenic extracts tested at the same time should be considered invalid and be repeated.
• Fire Ant:  Percutaneous testing is considered positive when the response occurs at a concentration of 1:100 w/v or less.4

2.2.2 Intradermal (Intracutaneous) Skin Test

Always perform percutaneous tests prior to intradermal skin tests.1, 2

Dose

Perform intradermal tests with at least 100-fold less concentrated solutions than the stock concentrates used in percutaneous tests [see Preparation and Administration (2.1)].

Fire Ant:  Use 0.02 mL of a 1:100,000 v/v dilution of the concentrate for intradermal tests.  Very sensitive individuals such as those who have had nearly fatal anaphylactic reactions may not tolerate even 1:100,000 v/v dilution of concentrate as a starting point.  These patients should be tested with a 1:10,000,000 v/v dilution of concentrate [see Preparation for Administration (2.1)].

Use intradermal tests following a negative or equivocal percutaneous test when the patient continues to report a history of symptoms following exposure to a specific allergen.

Administration

Intradermally inject 0.02 mL of the allergen using a 1 mL intradermal testing syringe with a 26 or 27 gauge, 1/2" or 3/8" needle with intradermal bevel, graduated in 0.01 units.  Insert needle at a 30˚ angle, bevel down.

Test concurrently with a positive histamine control at intradermal strength (0.1 mg/mL of histamine base) and an aqueous buffer negative control (Sterile Albumin Saline with Phenol, Sterile Buffered Saline with Phenol).

Interpreting Results

For interpretation of intradermal skin tests, follow the information provided in Allergy Diagnostic Testing:  An Updated Practice Parameter.1

• Measure wheal responses for the histamine positive control test and allergen tests at 10‑15 minutes after injection
• Response to the positive control should be at least 3 millimeters larger than the response to the negative control.
• The negative control (50% glycerin solution) response should measure < 3‑mm wheal and ≤ 10 mm flare (erythema).
• If either the response to the histamine positive control or to the negative control do not meet the criteria above for acceptable wheal size, the results for the allergenic extracts tested at the same time should be considered invalid and be repeated.
• Fire Ant:  Intradermal testing is considered positive when the response occurs at a concentration of 1:1,000 w/v or less.4

2.3.1 Dose Build-up

Following the first administration of 0.03 mL of the selected initial dilution of allergenic extract, dosing is increased in 0.03 mL to 0.12 mL increments until 0.3 mL is reached, following which 0.03 mL is administered from the next most concentrated allergen extract or allergen mixture vial in the dilution series.  The interval between doses is usually 3 to 7 days during dose build-up.  Proceed in this manner until a maintenance dose is reached.  The final maintenance dose may not be the target maintenance dose selected at the beginning of therapy.

The following adjustments may be necessary during dose build-up:

• If allergic symptoms or local reactions develop shortly after dose administration, decrease the dose volume to one-half or one-quarter of the maximum dose previously attained.
• If the patient is experiencing any seasonal allergy symptoms, decrease the dose volume to one-half or one‑quarter of the maximum dose previously attained.
• Adjust the dose periodically based on the patient’s tolerance and reaction.
• Decrease the dose if the previous injection resulted in a marked local reaction.
• Repeat the previous dose or reduce the dose at the next administration if local reactions persist for longer than 24 hours.
• Decrease the dose if the previous injection resulted in a systemic reaction.Any evidence of a systemic reaction is an indication for a significant (at least 75%) reduction in the subsequent dose or the cessation of immunotherapy.
• Repeated systemic reactions, however mild, are sufficient reason for the cessation of further attempts to increase the reaction-causing dose.

2.3.2 Maintenance Dose Selection, Adjustments, and Intervals

The maintenance dose is the dose that provides therapeutic efficacy without severe adverse local or systemic reactions.  This dose may be limited by adverse reactions and may not be the original targeted maintenance dose.  Select a maintenance dose based on the patient's clinical response and tolerance.

• Suggested maintenance dose is 0.3 mL of the undiluted allergen extract.  Occasionally, higher doses are necessary to relieve symptoms.
• Maintenance doses larger than 0.3 mL of undiluted allergen extract may cause patient discomfort due to the 50% glycerin content.
• After the maintenance dose is achieved, increase the injection interval to 2 weeks, then 3 weeks, and finally 4 weeks, as tolerated.  Administer the maintenance dose at a given interval three or four times before further increasing the interval to assure that no reactions occur.  Protection may be lost rapidly if the interval between doses is more than 4 weeks.

The following adjustments to the maintenance dose may be necessary.

 Withhold immunotherapy and/or reduce dosage, if any of the following conditions exist:

• Severe symptoms of rhinitis and/or asthma.  Decrease dose to one-half or one-quarter of the maximum dose previously attained if the patient has any seasonal symptoms.
• Allergic symptoms or a local reaction following the prior dose.
• Infection accompanied by fever.
• Exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection.

In situations prompting dose reduction, a cautious increase in dosage can be attempted once the reduced dose is tolerated.

Decrease the interval between doses if symptoms develop before the next injection is scheduled.

In some patients, the dosage may be increased and/or the dosing interval shortened based on individual responses and dosing requirements.  If the onset of symptoms is soon after the initiation of immunotherapy, decrease the interval between each dose.

Changing to a different lot of extract:  All extracts can lose allergenic activity over time and extracts vary in allergenic activity.  Two different lots of extract could differ substantially in allergenic activity, even if they are the same formula and concentration.  The volume of the first dose from the new vial should not exceed 50% of the previous dose.  Do not use extracts beyond their expiry date.

Changing to a different formulation of extract or to an extract from a different manufacturer:  Decrease the starting dose of the new extract when the extract is the same formula and dilution as the one previously used.  In general, a volume dose reduction to 50% of the previous product dose is adequate, but each situation must be evaluated separately considering the patient's history of sensitivity, tolerance of previous injections, and other factors.  If the patient tolerates the 50% decrease, then raise the next dose to the previous tolerated dose amount.  To re-establish the maintenance dose the starting interval between doses should not be greater than one week.

Prolonged period has elapsed since the last injection:  Patients may lose tolerance for allergen injections during prolonged intervals (> 4 weeks) between doses.  The duration of tolerance is an individual characteristic and varies from patient to patient.  In general, the longer the lapse in the injection schedule, the greater dose reduction required.

Changes made in the extract concentrate formula:  Changes other than those listed above such as a difference in extracting fluid (e.g., change from non-glycerin extracts to 50% glycerin extracts), combining two or more stock concentrates, or any other change can affect a patient’s tolerance of the treatment.  Extra dilutions are recommended whenever starting a revised formula.  The greater the change, the greater the number of dilutions required.

Duration of Treatment

The duration of treatment for immunotherapy has not been established.  A period of two to three years of injection therapy constitutes an average minimum course of treatment.  Evaluate patients for treatment response at least every 6 to 12 months while they receive immunotherapy.