Immunotherapy Flashcards
When Should Patient Discontinue a Course of Immunotherapy?
1) Injections have been administered for a minimum of 3 years (5 years for severe grass pollen allergy).
2) Most of the injections have been in the maintenance range, with Ag concentrations in the 5 mL treatment vial of at least a #1 dilution (0.2 mL of a #1 dilution or concentrate for each treated Ag, mixed into a 5 mL treatment vial)
3) Symptom relief has been enjoyed through all seasons of significance in the past year
From: Allergy in ENT Practice: The basic guide, 2nd Ed, 2005
How to Manage Restarting Immunotherapy
If restarting Immunotherapy after a cessation of therapy:
1) Within 6-8 weeks:
- Restart at 1/2 dose and re-escalate
2) After more than two months:
- Intradermal vial test should be given prior to attempting to re-institute subcutaneous injections
3) After 2-12 months:
- Re-make a new treatment vial and check sensitivity with a vial test
4) After more than one year:
- Re-evaluation and retesting is the safest approach, since unpredictable changes in skin sensitivity, environment, and allergic load may have occurred
How Long Should a Patient Receive Immunotherapy?
1) Most practices treat patients for 3-5 (mean 3.8 years) years before an attempt was made to stop treatment.
2) WHO states that the efficacy of immunotherapy beyond 3-5 years has not been demonstrated.
3) Relapse rates are between 0-55% after immunotherapy (Cox L, Cohn JR, Ann Allergy Asthma Immunol 2007; 98: 416-426)
Are There Any Age Limits on Immunotherapy?
1) There are no absolute upper or lower age limits
2) Studies have demonstrated similar efficacy in both children and adults
3) Safety in children under 5: only 1 systemic reaction in 239 patients < 5yrs old receiving 6689 injections = 0.00015%
4) Age should not preclude immunotherapy (2011 AAAAI position statement on allergen immunotherapy).
Immunotherapy in Pregnancy?
1) Immunotherapy may be continued, but is usually not initiated during pregnancy
2) Many MDs choose not to escalate immunotherapy during pregnancy, but there is little data to support this practice.
3) If pregnancy occurs during early buildup phase and patient is receiving a dose that is unlikely to be therapeutic, then it may be prudent to discontinue
4) There is no evidence of increased risk to mother or child while breastfeeding.
4 Step Strategy for Withdrawal of Immunotherapy.
1) Weekly maintenance injections for one year
2) If symptoms are controlled, lengthen to every two weeks for one year
3) If symptoms are controlled, then increasing the interval even further, to 3 or 4 weeks is reasonable
4) If patient is symptom free for a year on an every 3-4 week (usually Q 4 weeks) schedule, consider stopping immunotherapy.
Withdrawal of Immunotherapy
1) Begins with lengthening of the time interval between injections after the most significant allergen season has come to an end
2) Use the patient’s symptoms as a guide.
3) Begins with lengthening of the time interval between injections after most significant allergen season has come to an end
Maintenance Dose Recommendations
1) Try to advance to 0.5 mL from a vial containing 0.2 mL from ‘concentrate’ for each antigen
2) For Cat, may need 1 mL from ‘concentrate’ in maintenance vial.
3) If not tolerated, highest dose tolerated with arm reactions < 25 mm (Optimal) or < 50 mm (Maximal).
4) If not at least able to escalate to a vial of 0.2 mL of a #1 concentration, efficacy not clear
Immunotherapy ‘Optimal Dose’
1) Targets arm reactions < 25 mm in size
2) Upward or downward adjustment of maintenance immunotherapy doses is acceptable
What is the Maximally Tolerated Dose of Immunotherapy?
1) The local reaction produced signals that further advancement would be imprudent, while symptom relief is still being provided
2) Local arm reactions between 25 mm and 50 mm in size, but not systemic symptoms. Reduce the dose if > 50 mm
3) Some physicians will escalate 5X higher (1.0 mL of each antigen concentration in the 5 mL vial).
What Molds Should You Test For?
1) Always test for:
- Alternaria
- Aspergillus
- Cladosporium/Hormodendrum
- Helminthosporium
- Penicillium
2) Add less than 5 common molds: Curvilaria, Epicoccum, Fusarium, Mucor, Phoma, Pullularia, Rhodotorula, and smuts/rusts
What General Allergens Should You Test For?
1) Always test for:
- Cat
- Dog
- Cockroach
- D. Ptgeronyssinus/D. Farina
- Mold mix or selected molds
2) Consider testing for:
- Local molds/mites
- Other animals: horse, rabbit, rodent, livestock
What is Oral Allergy Syndrome?
1) Inhalant-Food cross reactivity
2) Fresh fruit, vegetables, nuts
3) Implications:
- Increased symptoms of oral itching during pollen/food season
- Allergies to specific antigens can suggest foods to avoid
Oral-Allergy Syndrome: what food allergies are associated with a Birch tree inhalant allergy?
- Apple
- Celery
- Carrot
- Zucchini
- Hazelnut
- Pear
- Peach
- Plum
- Cherry
- Strawberry
- Orange
- Persimmon
Ragweed Oral-Allergy Syndrome: what food allergies are associated with Ragweed allergy?
- Melons
- Banana
Mugwort Oral-Allergy Syndrome: what food allergies are associated with Mugwort inhalant allergy?
- Celery
- Coriander
Asthma and Immunotherapy
1) Poorly controlled asthma leads to increased risk for systemic reactions
2) Fatal and non-fatal systemic reactions are more common in patients with poorly controlled or severe asthma
3) Carefully consider assessment of asthma control at each injection visit
IDT (Intradermal Testing) Pros/Cons
1) IDT is the most accurate allergy test
2) Safe
3) Potentially lots of needles
4) Lengthy for staff and patient
5) May allow SCIT to begin at a more concentrated level
6) No ‘superiority’ shown over other methods
7) Minimal insurance acceptance
Skin Prick Testing Pros/Cons
1) Rapid
2) Safe
3) Good insurance acceptance
4) Good specificity, less sensitivity
5) Possible abnormal skin response
6) May miss lower sensitivity Ags
7) Must start immunotherapy at a more dilute concentration
Discontinuing Immunotherapy - Summary
1) Injections have ben administered for a minimum of three years (five years for severe grass pollen allergy)
2) Most of the injections have been in the maintenance range, with antigen concentrations in the 5 mL treatment vial of at least a #1 dilution (0.2 mL of a #1 dilution or concentrate for each treated antigen, mixed into a 5 mL treatment vial).
3) Symptom relief has been enjoyed through all seasons of significance in the past year
Source: King HC, Mabry RL, ‘Allergy in ENT Practice: The Basic Guide, 2nd Ed.
Immunotherapy in Immunodeficiency
1) No controlled studies about efficacy or risk
2) Marshall suggests the following guidelines for treatment of HIV + patients:
- CD4 count > 400
- No h/o opportunistic infection of AIDS-associated pathology
- Monitoring every 3 months
2) AAAAI 2011 Allergen Immunotherapy practice parameter: ‘Immunotherapy can be considered in patients with immunodeficiency and autoimmune disorders.’
Source: Marshall GD Jr. Allergy Asthma Proc 1999; 20:301-4, IV.
What Is A Plateau Response in Allergy Testing?
1) True Endpoint here is the second #7
5mm; 5mm; 7mm; 7mm; 9mm
2) The true endpoint is shown in this plateau reaction, since there is a negative response, followed by a positive response, followed by a confirming wheal. The positive wheal that immediately precedes the confirming wheal is the endpoint because it is the dilution that initiates progressive whealing.
Restarting Immunotherapy
1) Within 6-8 weeks
- Restart at 1/2 dose and re-escalate
2) After more than two months
- Intradermal vial test should be given prior to attempting to re-institute subcutaneous injections
3) Two - twelve months
- Re-make a new treatment vial and check sensitivity with a vial test
4) More than one year
- Re-evaluation and retesting is the safest approach, since unpredictable changes in skin sensitivity, environment, and allergic load may have occurred
Duration of Immunotherapy
1) Practices surveyed by Hurst, et al reported that their patients were treated for 3-5 years (mean 3.8) before an attempt was made to stop treatment
2) WHO states that efficacy of immunotherapy beyond 3-5 years has not been demonstrated
3) Published relapses 0-55% after immunotherapy
4) This topic is largely unstudied
- Use patient symptoms as a guide
- Many feel that a two to three year period of reduced or symptom-free seasons is first necessary, and 3-5 years of treatment may be desirable in order to effect lasting benefits
Source: Cox L, Cohn JR. Ann Allergy Asthma Immunol 2007; 98: 416-426
Symptom Relieving Dose
1) Definition: the dose of immunotherapy associated with patient-reported subjective symptom relief lasting for at least one week
2) A maintenance dose based on only symptom relief is felt to be potentially inadequate.
- Not as well correlated with improvements over placebo
- Not as well correlated with immunologic changes
Low Dose Immunotherapy
1) Rinkle - Maintenance dose could be predetermined by quantitative skin testing, by advancing only to 0.50 mL doses of the endpoint dilution.
2) Low dose immunotherapy fails to improve allergy symptoms vs. placebo
3) Low dose immunotherapy fails to change immunologic markers
Source: Van Metre TE Jr et al. A comparative study of the effectiveness of the Rinkel method and the current standard method of immunotherapy for ragweed pollen hay fever. J Allergy Clin Immujnol 1980;66:500-13.
Cumulative Dose and Efficacy of Immunotherapy
1) Cumulative dose - total amount of antigen received during immunotherapy.
2) Clinicians noted higher degrees of protection from allergen challenges when higher quantities of antigen were administered.
3) It is currently felt that a positive relationship exists between cumulative dose and efficacy.
- Quicker escalations
- Higher maintenance dose goals
How do you determine maintenance dosing of Immunotherapy?
There is no test to determine the:
- Maintenance dose of immunotherapy
- The cumulative dose of immunotherapy
- The duration of immunotherapy
What are the goals of Immunotherapy?
1) Immediate symptom relief
2) Prolonged symptom relief
3) Alterations in the immune system
- Increase in antigen specific IgG
- Blunting of IgE increases
- Change in T-cell response to antigen: Decreased Th2 response relative to Th1
4) Escalate to the dose that provides maximum benefit, tolerable risk
Mixing Vials: how to get to 10% final concentration Glycerin in the treatment vial.
1) Usually add 1mL of 50% Glycerin to the treatment vial to reach a final concentration of 10%.
- 1mL of 50% glycerin in 4mL phenolated saline = 10% glycerin
2) Each antigen added that is at concentrate has to be counted against the 1mL total of added glycerin
- 0.2mL Ragweed concentrate + 0.2mL of Timothy grass concentrate = 0.4mL of 50% Glycerin.
- 0.4mL of 50% glycerin from the concentrate Ag’s added + 0.6mL of the 50% glycerin = 1mL of 50% glycerin. This is what you add to the treatment vial to get your final concentration of glycerin to be 10%
Glycerin use In Mixing Allergy Treatment Vials
1) 2% Glycerin: #2 dilution of 50% Glycerin is used as the control for intradermal skin testing
2) 10% Glycerin in treatment vials confer 12 weeks of use (historical/traditional teaching)
3) 50% Glycerin in extracts frequently irritating intradermally or SQ (control for SPT)
How to Manage Escalation and Patient Compliance
1) Missed one week - repeat dose
2) Missed two weeks - reduce dose
3) Missed 3-4 weeks during buildup - repeat vial test
4) Consistent non-compliance results in failure to escalate and ineffective immunotherapy
What to do about local reactions to immunotherapy that occur during escalation.
1) If larger than 25-35 mm: give the same dose
2) If larger than 35-40 mm: decrease the dose
3) Late reactions:
- Mild: give same dose
- Severe: decrease the dose
4) If reactions last longer than 24 hours, use caution
What factors to consider during escalation - Is it safe to inject this week? Should I escalate, use the same dose, or use a lower dose?
Factors to Consider:
- Local reactions
- Seasonal change
- Changes in health
- New medications
- Asthma control
Accelerated immunotherapy for allergic rhinitis?
1) Accelerated immunotherapy is not indicated for allergic rhinitis. You are increasing the risk of a life threating complication for a non-life threatening disease
2) Indications for accelerated immunotherapy:
- Insect sting immunotherapy with high risk of another sting occurring within a short time period
- ASA desensitization
- Antibiotic desensitization
- Life threatening asthma
- Recurrent anaphylaxis from an inhalant trigger
Accelerated Immunotherapy - what is it?
1) There are various forms of accelerated (rapid, rush, or cluster) immunotherapy that may be used.
2) Maintenance can be reached in as little as one week.
3) There is a higher risk of anaphylaxis.
How to advance immunotherapy doses.
1) Each 5-7 days, advance the dose by 0.05 mL increments from 0.05mL to 0.5mL
2) Injections greater than 0.5mL in volume are usually uncomfortable
3) After 0.5mL volume has been reached, mix a new treatment vial containing 5X stronger dilutions
4) The antigen volume on the next injection from this new vial can then be in the 0.05 to 0.1mL range
5) This allows for continued dosage escalation, but always in the low volume range of 0.05 to 0.5mL
Allergen Immunotherapy Goals
1) Must deliver an adequate dose of each antigen
2) Must be administered for an appropriate length of time (generally 3-5 years)
3) May result in recurrence of symptoms if therapy is discontinued prematurely
Treatment Vial Preparation
1) Be compulsive when preparing treatment vials
2) Nurse/tech should not be interrupted
3) A second nurse or tech should double-check the calculations and initial
4) Write legibly, chart thoroughly
5) Date and initial the work
6) If the vial must last 3 months, then try to achieve a 10% glycerin concentration
Multiple Treatment Vials
1) Do not put more than 10-12 antigens/vial
2) High and low sensitivity antigens may require different rates of dose escalation
3) Grass and molds can slow advancement
4) Document the reason for splitting vials
- Affects reimbursement
- Patients prefer fewer injections
Intradermal ‘Vial Test”: How? Technique and Interpretation.
1) Produce a 4mm wheal with the treatment vial solution and read after 10 minutes.
2) If wheal growth is < 13mm, give the first dose
3) If the resulting wheal is > 13mm, dilute the vial with 1mL from the vial and 4mL of diluent and either retest or give the first dose.
Sources:
- King, Mabry, Mabry: Allergy in ENT Practice, 1998, pp 211-235
- Skin Testing for Inhalant Allergy: Current Strategies. AAOA Monograph; John H Krouse, Richard L Mabry, MD
Why Do We Perform A Vial Test?
1) 0.01mL is safer than 0.05mL
2) As a safeguard against mixing errors
3) Change in potency with new vs old vial
4) Change in potency between lots and manufacturers
Note:
- A good safety practice, but high level evidence is lacking
- Supported by the AAOA clinical care statement
- Be familiar with payor polices
What is an Intradermal Vial Test?
1) 0.01 mL intradermal wheal test dose (rather than a 0.05mL subcutaneous starting dose)
2) ‘A biologic indicator of tolerance to the mixed antigen vial.’
Source: AAOA Clinical Care Statement
What is ‘Prick-based’ Immunotherapy?
1) Commonly used for the diagnosis of inhalant allergy and the provision of immunotherapy
2) With a vial test, immunotherapy based on prick testing alone can be safe and effective
3) If the prick is positive, start treatment as #6 endpoint (c/w MQT approach).
Sources:
- Skin Testing for Inhalant Allergy: Current Strategies. AAOA Monograph; John H Krouse, Richard L Mabry, MD
What is the “RAST minus one” technique of determining the endpoint with RAST testing?
1) A patient has a class 4 RAST score to Ragweed
2) Ideally, if patient was IDT tested, (s)he would likely endpoint on a #4 ragweed
3) “RAST minus 1” assigns a starting endpoint of #5, not #4, so the starting dose is 5X more dilute
4) The five fold dilution provides a margin of safety
5) Essentially, a 10 week delay in therapy for safety
