immunotherapy

Immunotherapy

Reviewed by Sirapassorn

Sornphiphatphong, MD.

Immunotherapy

• Definition

• Indication

• Mechanisms of immunotherapy

• Clinical efficacy

• Immunotherapy administration

• Allergen extract selection

• Allergen extract handling

• Special considerations in immunotherapy

Immunotherapy

• In 2011 the allergy community celebrated the

one hundredth anniversary of the initial

description of immunotherapy by Leonard Noon

and John Freeman

• In the 1950s and 1960s, adequately controlled

studies were conducted in England by Frankland

and Augustin and in the United States by Lowell

and Franklin

Middleton 8th

Allergen immunotherapy

• Repeated administration of specific allergens

to patients with IgE mediated conditions

• For protection against the allergic symptoms

and inflammatory reactions associated with

natural exposure to these allergens

• Hyposensitization, allergen-specific

desensitization

Practice parameters 3rd JACI 2011

Indication of Allergen immunotherapy

• Allergic rhinitis

• Allergic conjunctivitis

• Asthma

• Hymenoptera sting hypersensitivity

New indications (2011):

• Atopic dermatitis with aeroallergen sensitization

• VIT: patients who experience recurrent bothersome large local reactions



AR, ARC

• Poor response to pharmacotherapy or Ag avoidance

• Unacceptable adverse effects of medications

• Desire to avoid long-term pharmacotherapy and reduce the cost of medication

• Coexisting allergic rhinitis and asthma

• Possible prevention of asthma in children

Asthma

• Poor response to

pharmacotherapy or Ag

avoidance

• Unacceptable adverse effects

of medication

• Desire to avoid long-term

pharmacotherapy and reduce

the cost of medication

• Coexisting allergic rhinitis and

allergic asthma

Practice parameter 2nd JACI, 2007

Hymenoptera sting hypersensitivity

• Hx of a systemic reaction and evidence of

clinically relevant specific IgE Ab

• Patients >16 yrs with a Hx of a systemic reaction

limited to the skin and evidence of clinically

relevant specific IgE Ab

• Adults and children with a Hx of a systemic

reaction to fire ant and evidence of clinically

relevant specific IgE Ab


Mechanisms of immunotherapy

Immunologic response to IT

• Immunologic changes complex

• Block both the immediate and late-phase allergic

response

• Decrease the recruitment of mast cells,

basophils, and eosinophils in the skin, nose,

eye, and bronchial mucosa after provocation or

natural exposure to allergens

• Successful immunotherapy associated with a

change toward a TH1 CD4+ cytokine profile


Middleton 8th

Humeral response

Immunoglobulin E

• Initially increase in specific IgE antibody levels

• Followed by a gradual decrease to a level that is

still higher than that present before treatment

• Clinical improvement develops before decreases

in their IgE antibody

• Whose IgE antibody levels never decrease,

thereby demonstrating that efficacy

Efficacy from immunotherapy is not dependent

on reduction in specific IgE levels

Middleton 8th

Practice parameter

Immunoglobulin G

• Increase serum allergen-specific IgG1 and IgG4

• Competition between IgG4 and IgE antibodies

for binding to the specific allergen

• Block IgE-dependent histamine release

• After stop IT, ↓IgG1 and ↓ IgG4 but clinical

improvement persisted

Not predictive of the duration and degree of

efficacy of immunotherapy


Middleton 8th

Immunologic tolerance

• Relative decrease in antigen specific

responsiveness, immune deviation, or anergy

• Relative decrease in allergen-specific

responsiveness and by the generation of

CD4+CD25+ regulatory T lymphocytes

• Producing IL-10, TGF-β


Middleton 8th

Specific allergen

• Effective for pollen, animal allergens, dust mite,

fungi, hymenoptera venom (honeybee, yellow

jacket, hornet, fire ants, wasp)

• Extract selection should be based on

- Hx in correlation with positive allergy skin test

or serum specific IgE Ab

- Clinically relevant allergen with exposure


Allergen extracts

Nonstandardized extracts • Vary widely in biologic activity

• Labeled as wt/vol (grams/ml), PNU

– a potency of 1:100 indicates that 1 g of dry allergen (eg, ragweed) was added to 100 ml of a buffer for extraction

– 1 PNU equals 0.01 g of protein nitrogen

• Neither method confers any direct or comparative information about an extract’s biologic potency

• not be considered equipotent

Allergen extracts

Standardized extracts

• Selection of a reference extract

• Selection of an assay or procedure to compare

the manufactured extract with the reference

extract

• More consistent biologic activity

• Less risk of an adverse reaction caused by

extract potency variability


Standardized extracts

•Potency of allergen extract by

• US: ID50EAL system Units

– BAU (bioequivalent allergy unit)

– AU (arbitrary units)

• Europe: Nordic system

ID50EAL; intradermal dilution for 50 mm

sum of erythema determines the

bioequivalent allergy units

ID50EAL system

• The quantitative skin test method for BAU

• The dilution that results in erythema size after

serial ID injecting 0.05 mL to 3 fold dilution of the

reference that end point 50 mm of erythema

• Mean D50 is calculated the potency of the

extract


Standardized extracts; US-licensed

• Aeroallergen: cat hair, cat pelt, dust mites

(D. pteronyssinus, D. farina), short ragweed,

Bermuda grass, Kentucky bluegrass, perennial

rye grass, orchard grass, timothy grass, meadow

fescue, red top, sweet vernal grass

• Hymenoptera venoms: yellow jacket, wasp

honey bee, yellow hornet, white-faced hornet


Principle of mixing allergen

immunotherapy

Consideration of the following:

(1) Cross-reactivity of allergens

(2) The optimal dose of each constituent

(3) Potential interaction between different

types of allergens; proteolytic enzymes


Cross-reactivity of allergen extract

• Limit the number of allergens in a vial to attain

optimal therapeutic doses of each components

• Cross-reactivity is variable for many grass and

weed pollens, their intrinsic allergenicity,

prevalence, and aerobiologic characteristics

within a specific region should be considered

• Single pollen within the cross-reactive genus or

subfamily that are maximally effective


Principle of mixing allergen

immunotherapy

Consideration of the following:

(1) Cross-reactivity of allergens

(2) The optimal dose of each constituent

(3) Potential interaction between different

types of allergens; proteolytic enzymes


The optimal dose

• The maintenance concentrate vial is the highest

concentration allergy IT vial (1:1 vol/vol)

• The projected effective dose; maintenance goal

• The maintenance dose is the dose that provides

therapeutic efficacy without significant adverse

local or systemic reactions and might not

always reach the initially calculated projected

effective dose


The optimal dose

Middleton 8th edition

Optimal maintenance dose:

5-20 mcg of major allergen for

inhalant allergens

Potential interaction between different types of allergens

• Many fungal extracts, cockroach extracts

contain proteases that are capable of

degrading the proteins in other extracts

with pollen, house dust mite, and dander

extracts

• not recommended to mix venoms together

Immunotherapy schedules

The build-up phase

• Starting doses: 1000- or 10,000-fold dilution of the maintenance concentrate

• Increasing amounts of the allergen

• 1-3 times a week

• Duration ranges from 3-6 months

The maintenance phase

• Begins when the effective therapeutic dose is reached

• The intervals between the injections are increased

• Every 4-8 weeks for venom

• Every 2-4 weeks for inhalant allergens


Middleton 8th edition Practice parameter 2nd JACI, 2007

Cluster immunotherapy

• Accelerated build-up schedule

• Several injections at increasing doses (generally 2-3

per visit), 30-min intervals

• Achieved more rapidly within 4 to 8 weeks

• Antihistamine 2 hours before dosing reduced local

and systemic reactions


Cluster immunotherapy

Middleton 8th edition Practice parameter 2nd JACI, 2007

Rush immunotherapy

• Increase doses of allergen at intervals 15-60

minutes over 1-3 days until the target

therapeutic dose is achieved

• Inhalant allergens associated with a greater risk

of systemic reactions

• Hymenoptera VIT have not been associated with

a similar high incidence of systemic reactions

Labeling



• Allergen extract and serial

dilutions

• ≥2 identifier; name, birth date

Duration of treatment

• Clinical improvement shortly after the patient

reaches a maintenance dose

• Evaluated at least every 6 -12 months

• No specific tests or clinical markers to the

relapse and remission after discontinuing IT

• Duration determined by the physician and

patient after considering the risks and benefits

associated with discontinuing or continuing IT

Safety

Local reactions

• Poor predictors of subsequent systemic

reactions at the next injection

• Dose reductions are unnecessary

• Not predict local reactions next injection

Large local reactions

• Defined ≥25 mm

• LLRs not predictive of future systemic reactions,

but 1/3 preceded systemic reactions

• LLRs 25-30 mm: repeat the dose

• LLRs 30-50 mm: reduce the dose for LLRs


Systemic reactions

• Less than 1% in conventional IT

• ~34% in some studies of rush IT

• AAAAI fatality rate 1:2.5 million injections

• Most serious systemic reactions occur within 30

minutes after an injection, patients should

remain in the medical clinic for at least 30

minutes after the IT injection

• The dose should be reduced after a systemic

reaction

Dose reductions

• After a systemic reaction

• During periods of exacerbation of symptoms

• When the interval between injections is

prolonged

• New vial

Dose reductions


Premedication

• Reduce the frequency of systemic reactions

caused by conventional IT, cluster IT, rush IT

• Increased the proportion of patients who

achieved the target maintenance dose

Premedication

• Oral nonsedating antihistamine 2 hr before

injection

– reduced the frequency of severe systemic

reactions caused by conventional IT and

increased who achieved the target maintenance

dose

– Reduced severe systemic reactions in cluster,

rush IT

– Decreased large local reactions

Nielsen L, et al. J Allergy Clin Immunol 1996;97:1207-13

Berchtold E, et al. Clin Exp Allergy 1992;22:59-65

Reimers A, et al. Allergy 2000;55:484-8

Premedication

LTRA

• Delays the onset and decreases the size of local reactions during rush VIT

• No controlled studies on the incidence of systemic reactions

Combination pretreatment

• Prednisone, an H1 and H2 histamine receptor antagonist before rush immunotherapy with inhalant allergens reduced a systemic reaction from 73% to 27% of patients

Wohrl S, et al Int Immunol 2007;144:137-42

Portnoy J, et al. Ann Allergy 1994;73:409-18

Shelly M, et al.AAAI 2004;92:414-419

Omalizumab pretreatment

• Fivefold decrease in the risk of anaphylaxis by

the rush immunotherapy

• Reduction in the rate of systemic reactions

during the weekly buildup phase, from 9.7% to

zero

Casale TB, et al. J Allergy Clin Immunol 2006;117:134-40

Omalizumab in combination

• Improve the safety and tolerability of

cluster and rush immunotherapy in

moderate persistent asthma and allergic

rhinitis

• Effective in improving symptom scores

compared with immunotherapy alone

Kopp MV, et al. J Allergy Clin Immuno 2002;110:728-35

Kuehr J, et al. J Allergy Clin Immunol 2002;109:274-80

Allergen selection and

handling

Allergen immunotherapy extract handling

(1) Storage temperature: 4-8oC

(2) Presence of stabilizers and bactericidal agents

(3) Concentration:

– more dilute concentrations, shorter shelf life

(4) Presence of proteolytic enzymes

(5) Volume of the storage vial

(1:1 vol/vol up to 1:10 vol/vol) when kept at 4oC

relatively constant and to be used until the

expiration date on the label

Allergen immunotherapy extract handling

• 0.03% HSA, 50% glycerin to maintain potency

• HSA prevent the loss of potency within storage vials by preventing absorption of allergen on the inner surface of the glass vial

• Glycerin

– preservative

– prevent loss of allergenic potency

– Inhibit the activity of proteolytic and glycosidic enzymes in certain extracts

– Pain when injected if >0.2 ml

• Phenol, preservative to prevent growth of microorganisms


Injection techniques

• Wiped with an alcohol to remove gross

contamination from the skin surface

• Calibrated small-volume syringe with a 26- to

27-gauge 1/2 or 3/8-inch nonremovable needle

• Subcutaneously in the posterior portion of the

middle third of the upper arm


Special considerations in immunotherapy

Immunotherapy in children

• Effective and well tolerated

• Prevent the new onset of allergen sensitivities or progression to asthma

• Can be initiated in young children

• Indications are similar to those of other age groups

• Difficulty cooperating with an IT program

• Consider the benefits and risks of immunotherapy

• Not considered in infants and toddlers because

– difficulty in communicating with the child regarding systemic reactions

– traumatic injection to very young children

Immunotherapy in Pregnancy

• Can be continued but is usually not initiated in

the pregnant patient

• Discontinuation IT if the pregnancy occurs

during the build-up phase and the pt is receiving

a dose unlikely to be therapeutic

immunotherapy

Health & Medicine

specific ige antibody

specific ige levels

immunologic response

allergic symptoms

children asthma poor

latephase allergic response

humeral response

ige mediated conditions