Immunotherapy Flashcards
(114 cards)
1
Q
When Should Patient Discontinue a Course of Immunotherapy?
A
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
2
Q
How to Manage Restarting Immunotherapy
A
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
3
Q
How Long Should a Patient Receive Immunotherapy?
A
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)
4
Q
Are There Any Age Limits on Immunotherapy?
A
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).
5
Q
Immunotherapy in Pregnancy?
A
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.
6
Q
4 Step Strategy for Withdrawal of Immunotherapy.
A
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.
7
Q
Withdrawal of Immunotherapy
A
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
8
Q
Maintenance Dose Recommendations
A
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
9
Q
Immunotherapy ‘Optimal Dose’
A
1) Targets arm reactions < 25 mm in size
2) Upward or downward adjustment of maintenance immunotherapy doses is acceptable
10
Q
What is the Maximally Tolerated Dose of Immunotherapy?
A
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).
11
Q
What Molds Should You Test For?
A
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
12
Q
What General Allergens Should You Test For?
A
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
13
Q
What is Oral Allergy Syndrome?
A
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
14
Q
Oral-Allergy Syndrome: what food allergies are associated with a Birch tree inhalant allergy?
A
- Apple
- Celery
- Carrot
- Zucchini
- Hazelnut
- Pear
- Peach
- Plum
- Cherry
- Strawberry
- Orange
- Persimmon
15
Q
Ragweed Oral-Allergy Syndrome: what food allergies are associated with Ragweed allergy?
A
- Melons
- Banana
16
Q
Mugwort Oral-Allergy Syndrome: what food allergies are associated with Mugwort inhalant allergy?
A
- Celery
- Coriander
17
Q
Asthma and Immunotherapy
A
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
18
Q
IDT (Intradermal Testing) Pros/Cons
A
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
19
Q
Skin Prick Testing Pros/Cons
A
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
20
Q
Discontinuing Immunotherapy - Summary
A
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.
21
Q
Immunotherapy in Immunodeficiency
A
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.
22
Q
What Is A Plateau Response in Allergy Testing?
A
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.
23
Q
Restarting Immunotherapy
A
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
24
Q
Duration of Immunotherapy
A
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
25
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
26
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.
27
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
28
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
29
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
30
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%
31
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)
32
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
33
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
34
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
35
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
36
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.
37
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
38
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
39
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
40
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
41
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
42
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
43
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
44
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
45
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
46
What is the meaning of "RAST minus 1"?
1) RAST = sIgE class (colloquialism)
2) RAST - 1 = more conservative starting dose
- IDT and sIgE levels don't correlate perfectly
- Antigens in extract not exactly the same as sIgE test
3) Initial dosing is started at a strength that is one dilution weaker than the In Vitro class sore (RAST minus 1 dilution, or R-1)
Source: Tandy JR, et al. Otolaryngol Head Neck Surg 1996; 115:42-5
47
How to dose immunotherapy starting dose from a RAST test
1) Mix a vial one endpoint more dilute than measured; a 5 fold dilution safety margin
2) If in vitro endpoint is #3, mix at endpoint #4
48
What is the correlation between specific IgE (RAST) and IDT (intradermal testing)?
1) Specific IgE tests are engineered (by adjusting the cutoff values) to correlate in a linear fashion and match the endpoints for intradermal skin testing.
2) Theoretically, if a patient has a class 4 sIgE (RAST) result, the patient's IDT endpoint would be expected to be a #4 dilution for that same antigen.
49
Specific IgE and IDT: Both surrogates for allergen sensitivity
1) Both IDT and specific IgE (sIgE) are quantitative tests
2) The IDT endpoint (EP) indicates the degree of skin reactivity to each tested allergen (related to the IgE bound to skin mast cells)
3) There is reasonable correlation between IDT and sIgE test results
50
What's In The First Treatment Vial?
1) A single antigen treatment vial is created by putting 0.2mL of a concentration 2 dilutions to the right of the endpoint dilution (25X more concentrated) in 4.8mL of diluent and glycerin
2) 0.05mL of this vial is less that what is used during IDT testing for that endpoint
3) A multi-antigen vial contains 0.2mL of each antigen from a concentration two dilutions "to the right," or 25X more concentrated than the endpoint. Then, dilute to a total of 5mL
4) 0.05mL of this vial is equivalent to 0.05mL of the original endpoint dilution for each antigen
51
Human Serum Albumin (HSA) as an alternative diluent
1) There is some evidence of superior stabilization of allergen extract, particularly dilute extracts
- Prevents adsorption of allergen to the vial glass
- Inhibits protein aggregation
- Nonspecific protein aggregation
- Nonspecific protein to compete for enzyme activity
2) Naturally occurring plasma protein - a derivative of human blood
- There is a concern about disease progression
- Expensive
Source: A Nida et al. Allergen stability of testing/treatment boards and immunotherapy vials with various diluents. IFAR 2015 Nov 5(11): 1028-35
52
What is the relationship between the cumulative dose of immunotherapy and the 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
53
Mixing treatment vials from a RAST test
1) Use the RAST minus one technique
2) There is a higher risk of anaphylaxis when injecting a patient with antigen based on a lab test: How do you account for this?
- Mix vial one endpoint more dilute that what is measured on the RAST test: this gives you a 5 fold dilution margin of safety
- e.g.: If in vitro (RAST) test endpoint is #3, then mix at endpoint #4
54
What is the correlation between RAST/Specific IgE testing and Intradermal (IDT) testing?
1) RAST tests are engineered (by adjusting the cutoff values) to correlate in a linear fashion and match the endpoints for intradermal skin testing
2) Theoretically, if a patient has a Class 4 sIgE test result, the patient's IDT endpoint would be expected to be a #4 dilution for that same antigen
55
Specific IgE and IDT: Both surrogates for allergen sensitivity
1) Both IDT and specific IgE (sIgE) are quantitative tests
2) The IDT endpoint (EP) indicates the degree of skin reactivity to each tested allergen (related to the IgE bound to skin mast cells)
3) There is a reasonable correlation between IDT ande sIgE test results
56
Glycerin as a preservative in treatment vials
1) Few studies on potency - Recommendations regarding use of preservatives and expiration dates are largely empiric and not strongly evidence based
2) The potency of extracts in a treatment vial (traditional teaching):
- Phenolated saline ONLY = about 6-8 weeks
- 10% glycerin concentration = about 3 months
3) 10% glycerin is usually well tolerated
4) Recommend adding enough glycerin to created a 10% glycerin concentration in the treatment vial
5) 1mL of 50% glycerin added to 4mL of phenolated saline - 10% glycerin
57
Preservatives in treatment vials
1) Phenol
- bacteriostatic
- marked decrease in potency when used alone
2) Human serum albumin (HSA)
- stabilizer
3) Glycerin
- stabilizer and bacteriostatic
4) Glycerin and HSA may have additive benefits
58
Factors Influencing Vial Potency
1) Storage temperature
2) Stabilizers and bactericidal agents
3) Concentration
4) Presence of proteolytic enzymes
59
Recipe for Vial Preparation
1) To create a 5 mL ten-dose/multiple antigen vial, use 0.20 mL of two dilutions stronger ("to the right") of the endpoint dilution for each antigen
2) Then add enough diluent +/- glycerin to make a 5 mL vial
60
Immunotherapy with Multiple Antigens: How do you mix so that the volume is not too high?
1) If you have multiple antigens that you want to treat, the injection volume with be too large, or you will have to give multiple injections
2) The solution is to use smaller volumes of stronger concentrations that can all be put in one treatment vial
61
Volume of antigens vs the number of antigens
5 mL of a #4 dilution contains the same number of antigen particles as 1 mL of a #3 dilution and 0.2 mL of a #2 dilution
62
10 Dose (5mL) Vial Quantities
1) Use the same formula for making vials escalation through maintenance
2) 3 month potency
3) 10 doses lasts 10 weeks
4) Escalate 0.05mL to 0.5mL
5) > 0.5mL volume of injection is uncomfortable
6) At maintenance, 0.5mL X 10 weeks = 5mL vial
63
Why is it that treatment can be safely initiated using 0.05mL of the endpoint dilution?
0.05mL of the endpoint is less antigen than the patient received during skin testing (IDT)
64
What are the five steps for five-fold dilutions?
1) Label vials filled with 4mL of diluent
2) Withdraw 1mL from the allergen extract bottle
3) Inject 1mL of stock antigen into the vial labeled '#1.' Mix thoroughly using syringe
4) Repeat the process by withdrawing 1mL from the #1 vial, injecting it into the vial labeled '#2.' Mix thoroughly
5) Continue the process through vial #6
65
Test/Treatment Board Preparation
1) Make up five-fold dilutions #1-#6 for each antigen
2) The test/treatment board diluent choice has traditionally been phenolated saline (PNS); you may also consider human serum albumin (HSA)
3) Start with 4mL of diluent in each vial
66
What are the advantages of IDT-based Immunotherapy?
1) It determines a patient's level of sensitivity for each antigen
2) The same extract is used in both testing and treatment.
3) It allows the clinician to give a tailored dose of each antigen for each individual patient
67
What are the disadvantages of IDT testing
1) Injecting suspected antigen into the patient
2) Affected by skin disorders or medication effect
3) Time commitment and lots of needle sticks
68
Methods of allergy testing according to precision
1) Intradermal dilutional testing (IDT) - 3 or more ID tests
2) In vitro varieties - Serum IgE quantified
3) IDT using extrapolation - 2 ID tests
4) Modified quantitative testing (MQT) - 1 prick + 1 ID test
5) Prick (alone) testing - 1 prick test only
69
Different testing methods can lead to different dosing, efficiency, and even safety of immunotherapy
IDT-based, In vitro-based, IDT using extrapolation-based, Modified quantitative testing (MQT)-based, and Prick testing can all be used to estimate allergen sensitivity and a safe starting dose
70
What are the indications for Immunotherapy?
1) IgE - mediated allergic disease
2) Symptoms and IgE results should be plausibly related
3) Pharmacotherapy and environmental controls should be insufficient
4) Are the patient's symptoms significant enough?
71
What are the goals of Immunotherapy?
1) Escalate antigen dose to the point of highest tolerated dose
2) Control symptoms without causing unacceptable local or systemic reactions
72
Immunotherapy Precautions
1) Allergic rhinitis is not life threatening
2) Immunotherapy is potentially life-threatening
3) Immunotherapy should not be undertaken haphazardly
73
What are Thommen's Postulates?
To be a clinically significant allergen, a plant must:
1) Be a seed-bearing plant
2) Produce large amounts of pollen
3) The pollen produced must be airborne
4) The pollen produced must be widely distributed
5) The pollen must be sensitizing
74
What is an allergen?
An allergen is a nonparasitic antigen capable of stimulating a type-I hypersensitivity reaction in atopic individuals
75
What is an Antigen?
An antigen is a molecule that prompts the generation of antibodies
76
What Allergy Testing Methods Can Be Used to Initiate Immunotherapy?
1) IDT-based testing
2) In-vitro based testing
3) IDT using extrapolation based testing
4) Modified Quantitative Testing (MQT) based testing
5) Prick (alone) based testing
Note: Testing methods can lead to different dosing, efficiency, and even safety of immunotherapy. All of the above testing methods can be used to estimate allergen sensitivity and a safe starting dose.
77
Allergy Testing Methods: Skin (in-vivo) vs Specific IgE (in-vitro) Testing
1) Skin (in-vivo) Testing (SPT alone, IDT alone, MQT)
- Immediate results
- Higher sensitivity
- Medication dependent
- Dependent on skin reactivity
- Risk of anaphylaxis
2) Specific IgE (in-vitro) Testing
- In office of send out lab
- Delayed results
- Not medication dependent
- Not dependent on skin reactivity
- Safer in high risk patients
78
Which causes of chronic sinusitis require immunotherapy?
1) Allergic Fungal Sinusitis
2) Central Compartment Atopic Disease
79
Should comprehensive rhinologic care address allergic disease?
Yes
80
Is there an increase in risk in a patient with Asthma who is on immunotherapy?
1) Poorly controlled asthma leads to increased risk for systemic reactions during immunotherapy.
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.
Source:
Lockey RF et al. Ann Allergy Asthma Immunol 2001; 87: 47-55
Bernstein DI et al. J Allergy Clin Immunol 2004; 113: 1129-36
81
Can you treat patient's with immunodeficiency with immunotherapy?
1) There are no controlled studies about efficacy or risk
2) Marshall suggests the following guidelines for treatment of HIV-positive patients
- CD4 count > 400
- No h/o opportunistic infection or AIDs-associated pathology
- Monitoring every 3 months
3) AAAAI 2011 Allergen Immunotherapy practice parameter: "Immunotherapy can be considered in patients with immunodeficiency and autoimmune disorders."
4) You should obtain clearance from the patient's treating physiciain.
Source:
Marshall GD Jr. Allergy Asthma Proc 1999; 20: 301-4, IV.
82
Immunotherapy in pregnancy.
1) Immunotherapy may be continued, but is usually not initiated during pregnancy.
2) While there is little data, many allergy docs choose not to escalate immunotherapy during pregnancy
3) If pregnancy occurs during early buildup phase and patient is receiving a dose unlikely to be therapeutic, then it may be prudent to discontinue until after delivery.
4) There is no evidence of increased risk to mother or child while breastfeeding.
Sources:
Cox L, et al. J Allergy Clin Immunol. 2011 Jan;127(1 Suppl): S1-55 (AAAAI 2011 Allergen Immunotherapy practice parameter)
83
Age and immunotherapy
1) There is no absolute upper or lower age limit for receiving immunotherapy
2) Studies have demonstrated similar efficacy in both children and adults
3) Safety study in children under 5 (Rodriguez et al) showed only 1 systemic reaction (urticaria) in 239 patients < the age of 5 receiving 6689 injections = 0.00015%
4) AAAAI Position Statement: "Age should not preclude initiation of immunotherapy
Sources:
Rodriguez et al. Rev Alerg Mex 2006; 53:47-51, III
Finegold I. Allergy Asthma Proc 2007; 28:698-705, IV
84
How to restart immunotherapy after a pause in treatment.
1) If the patient has been off of immunotherapy less than 6-8 weeks:
- Restart at 1/2 dose and re-escalate
2) If the patient has been off of immunotherapy more than two months:
- An intradermal vial test should be given prior to attempting to re-institute subcutaneous injections
3) If the patient has been off of immunotherapy two to twelve months:
- Re-make a new treatment vial and check sensitivity with a vial test
4) If the patient has been off of immunotherapy 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
Source:
King HC, Mabry RL, et al. Allergy in ENT practice: The basic guide. 2nd Ed. New York, Thieme; 2005
85
When should you discontinue immunotherapy?
1) The patient has been given allergy injections 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 5mL treatment vial of at least a #1 dilution (0.2mL of a #1 dilution or concentrate for each treated antigen, mixed into a 5mL treatment vial)
3) Symptom relief has been enjoyed through all seasons of significance in the past years
Source:
King HC, Mabry RL, et al. Allergy in ENT Practice: The basic guide, 2nd Ed. New York, Thieme; 2005
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How long should a patient receive immunotherapy?
1) Practices surveyed by Hurst, et al reported that their patients were treated for 3-5 years (mean 3.8 years) 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 of 0-55% after immunotherapy *
4) Many feel that a two to three year period of reduced of symptom-free seasons is first necessary, and 3 to 5 years of treatment may be desirable in order to effect lasting benefits
* Cox L, Cohn JR. Ann Allergy Asthma Immunol 2007; 98: 416-426
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What is the strategy should I use for withdrawal of immunotherapy?
Four Step Strategy for Withdrawal of Immunotherapy:
1) Weekly maintenance injections for one year
2) If symptoms controlled, lengthen to every two weeks for one year
3) If symptoms controlled, then increasing the interval even further, to 3 or 4 weeks is reasonable
4) if symptom free for a year on an every 3-4 weeks schedule, consider stopping immunotherapy
Note:
- There is little data to guide decisions
- Symptom assessment is the guide to withdrawal of immunotherapy
- Withdrawal begins with lengthening of the time interval between injections after most significant allergen season has come to an end
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Immunotherapy maintenance dose recommendations - how to get to maintenance therapy.
1) Try to advance to 0.5mL from a vial containing 0.2mL from "concentrate" for each antigen.
2) For Cat, may need 1mL from "concentrate" in maintenance vial.
3) If not tolerated, the highest dose tolerated with arm reactions < 25mm (Optimal) or < 50mm (Maximal).
4) If not at least able to escalate to a vial of 0.2mL of a #1 concentration, efficacy not clear.
89
What is the "Optimal Dose" in Immunotherapy?
1) The Optimal Dose is the dose that targets an arm reaction that is < 25mm in size.
2) You should adjust the maintenance dose of immunotherapy up or down to reach the optimal dose.
Source:
King HC, Mabry RL, et al. Allergy in ENT Practice: The Basic Guide, 2nd Ed. New York, Thieme; 2005
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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 25mm and 50mm in size, but not systemic symptoms. Reduce dose if the local reaction is > 50mm.
3) Some physicians will escalate 5X higher (1.0mL of each antigen concentrate in the 5mL treatment vial)
Source:
King HC, Mabry RL, et al. Allergy in ENT Practice: The Basic Guide, 2nd Ed. New York, Thieme; 2005
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What is the Symptom Relieving Dose of Immunotherapy?
1) The symptom relieving dose is the dose 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 probably inadequate/ineffective at long-term symptom control:
- Not as well correlated with improvements over placebo
- Not as well correlated with immunologic changes
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What is the Low Dose Immunotherapy Treatment Method?
1) This is mentioned for historical purposes only
2) Rinkel - maintenance dose could be predetermined by quantitative skin testing, by advancing only to 0.50 mL doses of the endpoint dilution.
3) Failure to improve allergy symptoms vs. placebo
4) Failure to change immunologic markers
Source:
Van Metre TE Jr et al. A Comarative Study of the Effectiveness of the Rinkel Method and the Current Standard Method of Immunotherapy for Ragweed Pollen Hay Fever. J Allergy Clin Immunol, 1980; 66:500-13
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Cumulative Dose of Immunotherapy and Efficacy
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 of immunotherapy:
- Quicker escalations
- Higher maintenance dose goals
94
When is an accelerated immunotherapy schedule indicated?
1) Accelerated immunotherapy can be used to treat insect sting allergies when there is a high risk of another sting occurring within a short time period
2) Can be used for Aspirin desensitization
3) Can be used in antibiotic desensitization
4) Can be used to treat life-threatening asthma
5) Can be used to treat recurrent anaphylaxis from an inhalant trigger
6) Accelerated immunotherapy IS NOT indicated in the treatment of uncomplicated allergic rhinitis: you should not use a treatment with increased risk to treat a benign disease
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Immunotherapy maintenance dose recommendations
1) Try to advance to 0.5mL from a vial containing 0.2mL from 'concentrate' for each antigen
2) For Cat, you may need 1mL from 'concentrate' in maintenance vial
3) If not tolerated, highest dose tolerated with arm reactions < 25mm (Optimal) or < 50mm (Maximal).
4) If not at least able to escalate to a vial of 0.2mL of a #1 concentration, efficacy not clear
96
Glycerin in antigen preparation - how to use:
1) 2% Glycerin:
- Use a #2 dilution of 50% Glycerin
- Use this as a control for intradermal skin testing
2) 10% Glycerin:
- 10% Glycerin in treatment vials preserve the antigens in vials for 12 weeks (historical/traditional teaching)
3) 50% Glycerin:
- 50% Glycerin in extracts is frequently irritating intradermally or SQ (control for SPT)
97
How to Manage Patient Non-Compliance During Escalation.
1) If the patient has Missed one week: repeat dose
2) If the patient has 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
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How to manage local reactions during immunotherapy escalation.
Escalation = The Art of Medicine:
1) If local reaction larger than 25-35mm: use the same dose next injection
2) If local reaction larger than 35-40mm: decrease the dose next injection
3) If the patient has a late reaction:
- Mile: use the same dose for the next injection
- If Severe: decrease dose for the next injection
4) If local reactions last longer than 24 hours, use caution
99
Decision Making During Escalation - the art of medicine.
1) Is it safe to inject this week? What are the factors that go into this decision?
- Local reactions
- Seasonal change: is this the patient's peak season?
- Changes in the patient's health?
- Is the patient taking any new medications?
- How well is the patient's asthma controlled?
2) Should I escalate, give the same dose, or should I use a lower dose?
100
Accelerated immunotherapy schedules for allergic rhinitis?
1) Accelerated immunotherapy schedules are not indicated for allergic rhinitis
- There is an increased risk of anaphylaxis with accelerated immunotherapy
- You shouldn't treat a non life-threatening disease with a therapy that increases risk of anaphylaxis
2) You can use accelerated immunotherapy schedules for the following clinical situations:
- Insect stings: you can use accelerated immunotherapy schedules in a patient with high risk of another sting occurring within short time period
- Aspirin desensitization: you can use accelerated immunotherapy schedules in aspirin desensitization
- Antibiotic desensitization
- Life threatening asthma
- Recurrent anaphylaxis from an inhalant allergy trigger
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What Is Accelerated Immunotherapy?
1) There are various forms of accelerated (rapid, rush, or cluster) immunotherapy that may be used
2) Maintenance therapy can be reached quickly in as little as one week.
3) There is a higher risk of anaphylaxis associated with accelerated immunotherapy schedules.
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How to advance immunotherapy.
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, 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 0.05mL to 0.1mL range
5) This allows for continued dosage escalation, but always in the low-volume range of 0.05mL to 0.5mL
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Should the first injection from the next immunotherapy treatment vial by 0.1 mL or 0.05 mL?
1) If 0.5 mL of the previous vial was well tolerated without reaction, then 0.1 mL of the next vial should be the antigenically equal dose from the next vial
2) Generally, we conservatively start with a 0.05 mL injection from the next vial to promote safety
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What are the 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
Sources:
Oto-HNS 1995; 113:597-602
Allergy 1996; 51:430-33
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How does one perform and interpret a "Vial Test?"
1) Produce a 4 mm wheal with the treatment vial solution and read after 10 minutes
2) If wheal growth is < 13 mm, give the first dose from treatment vial
3) If the resulting wheal is > 13 mm, dilute the vial with 1 mL from the vial and 4 mL of diluent and either retest or give first dose
Source:
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
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How To Perform a "Vial Test"
1) Give a 0.01 mL intradermal wheal test dose (rather than a 0.05 mL subcutaneous starting dose)
2) A vial test is a biologic indicator of tolerance to the mixed antigen vial
Source:
AAOA Clinical Care Statement
107
Prick based immunotherapy.
1) Prick testing is 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 patient is prick positive, start treatment as a #6 endpoint. This is c/w the MQT approach.
Source:
Skin Testing for Inhalant Allergy: Current Strategies. AAOA Monograph; John H. Krouse, Richard L. Mabry, MD
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How to mix/prepare vials from a RAST/in vitro testing.
Preparing a vial from an in vitro test is the same as from IDT except:
1) We use a more conservative starting dilution/endpoint.
2) Intradermal 'vial tests' are prudent
Source:
King, Mabry, Mabry: Allergy in ENT Practice, 1998, pp 211-235.
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Schedule for more rapid advancement of immunotherapy.
1) For use in 'properly selected' patients
2) Begin with initial treatment of 0.05 mL, then advance to 0.1 mL, and advance by 0.1 mL every 5 - 7 days
Schedule: Progress on this schedule at weekly intervals -
0.05 mL
0.1 mL
0.2 mL
0.3 mL
0.4 mL
0.5 mL
110
If you use this more rapid escalation schedule, you will reach the 0.5 mL injection volume in about 6 weeks.
1) Starting treatment vial:
- Week 1: 0.05 mL
- Week 2: 0.10 mL
- Week 3: 0.20 mL
- Week 4: 0.30 mL
- Week 5: 0.40 mL
- Week 6: 0.50 mL
2) Next vial 5X stronger than starting vial:
- Week 1: 0.05 mL
- Week 2: 0.10 mL
- Week 3: 0.20 mL
- Week 4: 0.30 mL
- Week 5: 0.40 mL
- Week 6: 0.50 mL
3) Next vial 25X stronger than starting vial and 5X stronger than previous vial:
- Week 1: 0.05 mL
- Week 2: 0.10 mL
- Week 3: 0.20 mL
- Week 4: 0.30 mL
- Week 5: 0.40 mL
- Week 6: 0.50 mL
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Dosage escalation - slow escalation vs rapid escalation.
1) If you escalate too slowly:
- There is a risk of no benefit
- Risk of patient non-compliance
2) If you escalate too rapidly:
- There is a risk of increased local reaction or anaphylaxis
- Take into account Antigens treated
- Take the season into account
- Take into account the patient's clinical status
112
Traditional escalation with multiple antigens using 1:5 dilutions.
1) Starting treatment vial:
- Week 1: 0.05 mL
- Week 2: 0.10 mL
- Week 3: 0.15 mL
- Week 4: 0.20 mL
- Week 5: 0.25 mL
- Week 6: 0.30 mL
- Week 7: 0.35 mL
- Week 8: 0.40 mL
- Week 9: 0.45 mL
- Week 10: 0.50 mL
2) Next vial 5X stronger than starting vial:
- Week 1: 0.05 mL
- Week 2: 0.10 mL
- Week 3: 0.15 mL
- Week 4: 0.20 mL
- Week 5: 0.25 mL
- Week 6: 0.30 mL
- Week 7: 0.35 mL
- Week 8: 0.40 mL
- Week 9: 0.45 mL
- Week 10: 0.50 mL
3) Next vial 25X stronger than starting vial:
- Week 1: 0.05 mL
- Week 2: 0.10 mL
- Week 3: 0.15 mL
- Week 4: 0.20 mL
- Week 5: 0.25 mL
- Week 6: 0.30 mL
- Week 7: 0.35 mL
- Week 8: 0.40 mL
- Week 9: 0.45 mL
- Week 10: 0.50 mL
Note: 0.5 mL of antigens in week 10 of a vial is antigenically equivalent to 0.10 mL of the next more potent vial (5X more potent)
113
How to prepare a vial from a RAST/In Vitro test using the "RAST minus 1" method.
Allergen Class R-1
Antigen A 4 #5 (0.20mL of #3)
Antigen B 5 #6 (0.20mL of #4)
Antigen C 2 #3 (0.20mL of #1)
Antigen D 3 #4 (0.20mL of #2)
______________________________________
Total Volume of Antigens (0.80mL)
Add 3.2mL of diluent + 1mL of 50% glycerin OR
4.2 mL of HSA to bring volume to 5.0mL
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Antigen Effective Dose Range
1) Dust Mites
- Labeled potency/concentration: 3000, 5000, 10,000, and 30000 AU/mL
- Probable Effective Dose Range: 500-2,000 AU
2) Cat
- Labeled potency/concentration: 5,000 to 10,000 BAU/mL
- Probable Effective Dose Range: 1,000 - 4,000 BAU
3) Grass, Standardized
- Potency: 10,000 - 100,000 BAU/mL
- Effective Dose Range: 1,000 - 4,000 BAU
4) Short Ragweed
- Potency: 1:10-1:20 w/v; 100,000 AU/mL
- Effective Dose Range: 1000 - 4,000 AU
5) Non-Standardized Extract - Dog
- Potency: 1:10-1:100 w/v
- Effective Dose Range: 15mcg of Can f1
6) Non-Standardized Extracts
- Potency: 1:10-1:40 w/v or 10,000-40,000 PNU/mL
- Effective Dose Range: Highest tolerated dose
Source: Cox L, et al. J Allergy Clin Immunol 2011:12127 (suppl) S25-85
