Immunotherapy workshop

Immunotherapy

Dr. Ali Ashur Tuati

Abu Setta Chest Hospital

Background

Allergen immunotherapy can provide:

-significant improvements in allergic symptoms

-reduce the need for additional pharmacotherapy.

Allergen immunotherapy has been clinically demonstrated to

provide long-term clinical benefits, including symptomatic

disease remission and a reduction in allergic disease

progression from rhinitis to asthma.

The first report describing immunotherapy was published in 1911,

when Noon described that the subcutaneous injection of a pollen

extract suppressed allergen-induced symptoms.

What is immunotherapy?

Immunotherapy is a treatment modality for IgE-mediated allergic disease. Incrementally increasing doses of specific allergen are given to an allergic patient over time. This consists of build-up phase with a specific allergen(s) in incremental increasing doses and this followed by a maintenance phase in which the patient receives a stable dose of specific allergen(s). Treatment is usually used for 3-5 years.

Tests for allergic patients

Radioallergosorbent testing (RAST)

Prick skin test

-It is a blood test. -It is highly specific but not sensitive as prick skin test

-Skin tests can be done by either percutaneous (prick)or intradermal method.-In Prick method allergen extract is placed on skin and a device is used to prick through the extract.-A positive control typically histamine to evaluate for appropriate reactivity, and negative control is used to evaluate for dermagraphism. -Intradermal method involves injecting small amount of allergen usually of Hymenoptera and drug allergy. It is used less frequently for environmental allergens because of Increased Sensitivity and Decreased Specificity.

Allergists use the results of both tests for writing “recipes” for patient-specific immunotherapy.

Which type of allergy immunotherapy is used?

-Aeroallergen immunotherapy (mainly)

-Foodallergen immunotherapy(rarely)

Units used to label antigen extracts

-Not all allergen extracts are labeled with same units.(1)-Standard allergen vaccines have an allergic content compared with a national reference.-In USA standardization is done with intradermal skin testing, known as ID50 EAL (intradermal dilution for 50-mm of erythema determines the bioequivalent allergy unit “BAU”). The dilution is chosen when 50 mm of erythema is observed to the tested extract. This testing is performed in people with known allergy to the tested allergen. Once the testing is completed , extracts are labelled with the same unit , bioequivalent allergy unit (BAU). In the past , they were labeled in patency units (PU) . Despite being standardized , Dust Mites are still labeled as PU rather than BAU.(2)-Non-standardized extracts are labeled as: -weight to volume (wt/vol) , OR in -protein nitrogen units (PNU) .These extracts vary in biologic activity.

Maintenance dose in immunotherapy

-After build-up phase patient will have maintenance phase i.e. maintenance dose of allergen extract.

-The maintenance dose is the typical amount of allergen tolerated to achieve a sustained clinical response .

-This dose has been estimated to range from 5 to 20 jgfrom most allergens, maintenance for hymenoptera venom tends to be higher at 100 jg.

-These doses are often tailored to individual symptoms or reactions .

-When patient reaches the maintenance dose the interval between injections can be increased to 4-6 weeks.

Benefits of immunotherapy

There is good evidence that allergen

immunotherapy is effective for the treatment of:

Allergic rhinitis

Allergic conjunctivitis

Asthma

Atopic dermatitis

Insect allergy (Hymenoptera)

Benefits of immunotherapy

-Multiple studies have demonstrated the effectiveness of allergen immunotherapy in these conditions for both children and adults.The degree of effectiveness may vary for the individual patient. -Clinical improvement should occur within or soon after the first year of treatment, and this benefit may improve with continued treatment. -The Allergen Immunotherapy Practice Parameters suggest that, “If clinical improvement is not apparent after 1 year of maintenance therapy, possible reasons for lack of efficacy should be evaluated. If none are found, discontinuation of immunotherapy should be considered, and other treatment options should be pursued.” -It has been observed that some patients may experience a worsening of their asthma, atopic dermatitis and allergic rhinitis or conjunctivitis symptoms during treatment, especially during the first few months of therapy.

Benefits of immunotherapy

-There is no consensus on when to discontinue aeroallergen immunotherapy, but benefits are often maintained for years after stopping therapy in some individuals, and indefinitely in others. -In grass-pollen allergy, 3-year course of subcutaneous immunotherapy gave prolonged relief of symptoms.-For many patients with stinging insect allergy, 3-5 years of treatment may be sufficient for sustained effectiveness after discontinuing therapy. -Patients experiencing more severe reactions to stings may be considered for longer durations of treatment, given the risk of the recurrence of a life-threatening reaction over time.

-Subcutaneous allergen immunotherapy is not used for patients with food allergies. Although studies have demonstrated an increased tolerance to peanut challenge in patients who received subcutaneous peanut immunotherapy, there was an unacceptably high incidence of systemic reactions (e.g., anaphylaxis) in most of the patients during treatment.

Adverse reactions to allergen immunotherapy

Adverse reactions to allergen immunotherapy do occur, including:

-local reaction,

-Systemic reaction, -Death from severe systemic allergic reactions. Although very rare, deaths associated with immunotherapy may be due to clerical and medical errors by healthcare personnel. Examples include administering a wrong dose or wrong extract to the wrong patient. Other factors that may contribute to immunotherapy fatalities include symptomatic asthma and delay in the administration of epinephrine during a systemic reaction.

Initial and ongoing training will improve the expertise of healthcare workers responsible for administering immunotherapy and, ultimately, the safety of their patients.

Complication Prevention• While adverse systemic reactions are uncommon, immunotherapy should be

administered by only trained personnel, and resuscitative medications and

equipment should be immediately available.

• Adequate equipment and medications should be immediately available in case of

anaphylaxis.The following are suggested equipment and medications for the

management of systemic immunotherapy reactions.

-Stethoscope and sphygmomanometer

-Tourniquet, syringes, hypodermic needles, and intravenous catheters (eg, 14-18 gauge)

-Aqueous epinephrine HCL 1:1,000 weight/volume

-Equipment to administer oxygen by mask

-Intravenous fluid setup

-Antihistamine for injection (second-line agents for anaphylaxis, but H1 and H2

antihistamines work better together than either one alone)

-Corticosteroids for intramuscular or intravenous injection(second-line agents for anaphylaxis)

-Equipment to maintain an airway appropriate for the supervising physician’s expertise and skill

-Glucagon kit available for patients receiving beta-blockers

Patient Instructions

• Prior to each allergy shot, it is recommended

that the health care provider confirm that:

-no reaction occurred during the preceding shot,

-the patient has begun no new medications,

(particularly beta-blockers), and that

-asthma, if present, is stable via peak flow

measurement.

Elements of Informed Consent

• Any medication (including beta-blockers) or health contraindications (eg, loss of asthma control) should be identified.

• Duration of treatment and symptom control should be discussed.

• Patients who become pregnant while on immunotherapy may continue treatment;

however, commencing immunotherapy in pregnant women is not advisable.

Some authors do not advance immunotherapy in pregnant women until the postnatal period.

• Subcutaneous immunotherapy should be initiated only in patients willing and

able to comply with weekly injections for a year or longer. Once maintenance is

reached, the injection regimen may become less frequent; however, several years’ duration is commonly required for clinical efficacy.

• Sublingual immunotherapy is appropriate for patients who are unable to commit to weekly injections or those who do not want injections.

• Interestingly, a 2013 study by Kiel et al demonstrated that long-term adherence

favored subcutaneous immunotherapy over sublingual immunotherapy.[30]

Pre-Procedure PlanningChoosing antigens to treat with immunotherapy

• Careful consideration must be given to the timing and

location of symptoms when choosing antigens to treat.

For example, a patient with spring-only symptoms who

allergic to trees and ragweed may not require

immunotherapy for ragweed. A patient with symptoms

that occur only when visiting homes where cats live

may not require treatment for their pollen sensitivities.

Testing should be based on a patient’s specific allergen

exposure.

Modalities of immunotherapy

1-Subcutaneous immunotherapy

2-Sulingual-sallow immunotherapy

3-Sulingual-spit immunotherapy

4-Oral immunotherapy

5-Inhaltion immunotherapy

6-Nasal immunotherapy

Types of subcutaneous immunotherapy

1-Standard schedule ( build-up phase given weekly and takes 3-4

months so that maintenance phase achieved slowly )2-Accelarated schedule (the build-up phase is much quicker so

that maintenance can be achieved rapidly):i-cluster immunotherapy ( involves 1 or 2 visits/week

with multiple escalating injections at each visit )ii-Rush immunotherapy (are designed to achieve

even more quickly than cluster schedules . Maintenance doses can be achieved in a matter of hours or days) .

iii-Ultra-rush immunotherapy Quicker schedules are much more commonly used for VENUM IMMUNOTHERAPY in high-risk people.

Rush and Cluster Immunotherapy

Rush and Cluster Immunotherapy represent accelerated schedules of immunotherapy. They are designed to allow a patient to reach a maintenance dose in a shorter time that the more traditional weekly immunotherapy. Though this may provide improved convenience, it also is associated with an increased risk of allergic reactions

Disadvantages of rush and cluster immunotherapy

Disadvantages of rush and cluster immunotherapy:

-There is increased risk of systemic reactions and should be reserved for Exceptional situations .

-Systemic reactions from rush venom protocols range from 0-67% . In addition systemic reactions occur at a longer time interval after last injection , therefore patients should be monitored for longer than the standard 20-30 min. recommended for standard schedules.

Cluster Immunotherapy

Cluster immunotherapy is an accelerated

version of traditional immunotherapy.

Allergy Partners’ standard conventional

immunotherapy build up schedule calls for

28 incremental doses given once or twice a

week. In Cluster, this build up period is

condensed into 8 ‘sessions’ held once or,

ideally, twice a week.

Cluster immunotherapy (rapid desensitization)

Cluster immunotherapy (rapid desensitization) is a method of accelerated desensitization utilizing allergy shots in clusters or groups one or two days a week until a maintenance dose is reached. This progression is usually accomplished in 5 or more weeks. It may be longer depending upon the rate of allergic reactions. Reaction rates using pre-medication are similar to conventional immunotherapy ranging from 0 to 33%. The advantage of an accelerated cluster immunotherapy program is achieving maintenance dose quicker but it involves a more concentrated time requirement in the first 5 or more weeks compared to conventional immunotherapy schedules. In addition, there may be a higher risk of allergic reactions but overall, appears to be comparable to traditional immunotherapy schedules. They both provide the same effectiveness once the maintenance dose is obtained.

Rush Immunotherapy

-Rush schedules can be used to reach a maintenance dose more quickly than weekly schedules

-Rush schedules are more rapid than cluster immunotherapy.

-An early study used a schedule that permitted patients to achieve a maintenance dose in 6 days; however, patients were required to remain in the hospital. As experience with accelerated forms of immunotherapy was acquired, schedules were developed to reach a maintenance dose more rapidly. -The most accelerated schedule that has been described for inhalant allergens involves administering 7 injections over the course of 4 hours. -Ultra-rush immunotherapy schedules have been described for stinging insect hypersesitivity to achieve a maintenance dose in as little as 3.5 to 4 hours. -The advantage of a cluster or rush schedule is that it permits patients to attain a therapeutically effective maintenance dose more rapidly than with a conventional schedule.

-Controlled studies have shown symptomatic improvement shortly after reaching maintenance doses by using cluster and rush schedules.

Indications for Rush and Cluster

Immunotherapy

Indications for accelerated schedulesWhile there are no firm indications for accelerated schedules, the

following patients and/or situations may benefit from such schedules:

Patients who have not been able to reach a maintenance dose

on weekly immunotherapy due to systemic reactions or due to

sub adherence

Patients whose schedule precludes weekly injections for a

prolonged time

Patients with asthma that cannot be adequately controlled but

who can be controlled long enough to reach a maintenance

dose with an accelerated schedule

Advantages and disadvantages of Rush

and Cluster Immunotherapy

Accelerated Immunotherapy schedulesThere a number of advantages and disadvantages to using an accelerated immunotherapy schedule:

AdvantagesMay be more convenient if the duration of weekly visits is shortened

Improved adherence

Clinical benefit may occur more rapidly

May be safer because the number of vials being used is reduced once a maintenance dose is reached

DisadvantagesThere is an increased risk of systemic reactions during the procedure

Increased time and resources are needed in the health facility to give multiple injections

Systemic Reactions to Rush schedules

Rush schedules are associated with an increased risk of systemic reactions. However, rush protocols for administration of Hymenoptera VIT have not been associated with a similarly high incidence of systemic reactions.

The advantages of rush immunotherapy come at a cost because there is an increased risk of local and systemic reactions.

Systemic reaction rates have been reported to be as high as 73% of patients, with the risk of such reactions reduced to 27% by premedication in one study. Most reactions to rush immunotherapy are not severe, and the most common systemic reaction is usually flushing. Systemic reactions with rush schedules have been reported to occur up to 2 hours after the final injection. For that reason, individuals receiving rush immunotherapy should remain under physician supervision for a longer waiting period than the usual 30 minutes recommended for conventional schedules (eg, 1.5-3 hours on the day of allergen immunotherapy extract administration). Rush protocols for administration of Hymenoptera venom have not been associated with a similarly high incidence of systemic reactions.

Premedication before Accelerated immunotherapy:Premedication is given in an attempt to reduce the risk and severity

of a systemic reaction during the procedure.

Factors that increase the risk of a systemic reaction include:

Poorly-controlled asthma

Extremely high sensitivity to the allergens

Poor suppression of skin reactivity with premedication

Cluster Immunotherapy (CI):It may be desirable to have the patient take an H1 and H2 antagonist

on the day that they will receive cluster injections, however,

there is no evidence that doing so reduces the likelihood or severity

of a local or systemic reaction.

:Rush Immunotherapy (RIT)Patients should receive prophylaxis for 3 days starting 1 day prior to the procedure to reduce the likelihood of a systemic reaction.

• Cetirizine• Diphenhydramine

H-1 antagonist

• RanitidineH-2 antagonist

• PrednisoneCorticosteroid

• MonteleukastLeukotriene receptor antagonist

Premedication Prophylaxis

Premedication should be given before cluster and rush immunotherapy with aeroallergens to reduce the rate of systemic reactions.

Premedication with a non-sedating antihistamine (loratadine) 2 hours before the first injection of each visit reduced both the number and severity of systemic reactions during cluster immunotherapy. Premedication with a 3-day course of prednisone, an H1 histamine receptor antagonist, and an H2 histamine receptor antagonist before rush immunotherapy with inhalant allergens reduced the risk of a systemic reaction from approximately 73% to 27% of patients.In one study designed to investigate the effect of 12 weeks of premedication with a humanized monoclonal anti-IgE antibody (omalizumab) on the safety and efficacy of rush immunotherapy, there was a 5-fold decrease in the risk of anaphylaxis in the group premedicated with omalizumab compared with the placebo premedication group. There are anecdotal reports of reductions in systemic reaction rates with the addition of a leukotriene receptor antagonist, but there have been no published studies.

Premedication

The following medication will be taken for 3 days, starting the day before the Rush immunotherapy:

-Prednisone 30 mg two times/day with a meal. (Children 1mg/kg)

-Xyzal 5 mg, 1 tablet in the morning. (Children ½ tablet)

-Zantac 150 mg, 1 tablet 2 times/day. (Children 3mg/kg/day under 12 years old)

-Singulair 10 mg, 1 tablet in the evening. (Children under 15 years old 5 mg)

Drink plenty of fluids to ensure adequate hydration.

A typical cluster immunotherapy schedule at Allergy & Asthma Care is as follows:Week 1: Two days of clusters (both 3 injections) with total time at least 1 ½ hours,

Week 2: Two days of clusters (3 injections, then 2 injections) with a total time at least 1 ½ hours and 1 hour respectively,

Week 3: One day of cluster (2 injections) with a total time at least 1 hour,

Week 4: One day of cluster (2 injections) with a total time at least 1 hour,

Week 5: One day of cluster (2 injections) with a total time at least 1 hour,

Week 6: One dose at maintenance with a total time at least 1 hour,

Week 7-10: One dose at maintenance at 5 to 7 day intervals and then slowly will be spread out to increasing intervals up to a maximum of monthly injections.

ClusterHourDayWeek

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13

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14

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15

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Cluster Immunotherapy (example)

Rush Immunotherapy(1-day schedule)

Protocols For Hymenoptera venom immunotherapy

Hymenoptera venom immunotherapy

-The time to reach maintenance dose depends on the protocol used . -Rush protocol provide more rapid protection, however slow protocols ae usually better tolerated. -Cluster protocol represents an alternative regimen.

The protocols indicated may be adapted to the reactivity of each patient.

Hymenoptera venom immunotherapy-Protocols

Ultra-Rush dose in microgram

HourDay

0.11

10203040

00.5

1 1.5

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5050

01

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10043

10071

10099

Maintenance dose reached in 6 weeks then every 4 weeks

RushDose in microgram

HourDay

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1

2.5

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2

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3

1004

1008

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Maintenance dose reached in 4 days then every week for 2 weeks , then every 2 weeks

for 4 weeks , the every 4 weeks

Cluster dose in micrograms

HourDay

0.0010,010.1

0 0.5

1

1

15

10

012

8

2030

12

15

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12

22

10029

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10092Maintenance dose reached in 4 weeks, then

every 4 weeks

Conventional dose in micrograms

HourDay

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1

12

01

8

48

01

15

1020

01

22

4029

6036

8043

10050

10057

10071

10085

100106

Maintenance dose reached in 7 weeks then after week ,then after 2 weeks, then after

3 weeks then every 4 weeks

sublingual tablet immunotherapy

• In April 2014, the FDA approved a sublingual tablet (Oralair) consisting of 5 calibrated

grass pollen extract. It contains Perennial Ryegrass (Lolium perenne), Kentucky

bluegrass (Poa pratensis), Timothy grass (Phleum pratense), Orchard grass (Dactylis

glomerata), and Sweet Vernal grass (Anthoxanthum odoratum). The Oralair SL tablet

needs to be administered 4 months prior to the season for the specific allergen.

• A second sublingual tablet (Grastek) for Timothy grass was also approved by the FDA

in April 2014 for adults and children aged 5 years or older. It should be administered

at least 12 weeks before the start of the grass pollen season. The efficacy and safety

in North America was established in a large study (n=1500) of adults and children

aged 5-65 years. Results showed a 23% improvement of symptoms in the entire

grass pollen season.

• A third sublingual immunotherapy tablet for ragweed (Ragwitek) was also approved in

April 2014 for adults aged 18 years or older. The effectiveness studies included about

760 patients. Phase 3 clinical trials showed that the tablet reduced rhinoconjunctivitis

symptoms over the entire season by 27-43% compared with placebo.

Conventional Immunotherpy

Allergens for immunotherapy

Already validated by control studies

Specific immunotherapy

Grasses Trees

Weeds

Pollens

D. PteronysinusD. Farinae

Storage mitesBiomia

Mites

CatDog

Epithelia

AlternariaCladosporium

Moulds

Recommendations for allergen mixtures

Allergen mixtures

MouldsEpitheliaMitesPollensAllergens

NoNoNoYesPollens

NoNoYesNoMites

NoYesNoNoEpithelia

YesNoNoNoMoulds

No-Unrelated allergens mixture not recommended by WHOYes-Related allergens mixture possible

Mixtures with related allergens

Stallergens recommendations:

-A reference can be either a single allergen or a mixture of several related allergens with a high degree of cross-reactivity .

-Stallergens does not recommend to mix more than 5 of these references.

Indications to immunotherpapy

Therapeutic indications:1-Type I allergies (Gell and Coombs classification) mainly comprise: -rhinitis , -conjunctivitis ,

-rhinoconjunctivitis,-asthma of a seasonal or perennal nature.

2-The goal of specific immunotherapy (SIT) is to prevent the clinical consequences of a contact between sensitized subject and the allergen when aetiological factors have been clearly identified.

SIT indications in allergic rhinitis according to ARIA position paper

Specific immunotherapySublingual route Subcutaneous route

ARIA position paper

not recommendedMild intermittent symptoms

IndicatedModerate / severe intermittent symptoms

IndicatedMild persistent symptoms

IndicatedModerate / severe persistent symptoms

SIT indications in allergic asthma according to WHO potion paper

Specific immunotherapySublingual route Subcutaneous route

WHO position paper 1998 Grade of asthma severity

not recommendedGrade 1 : intermittent

indicatedGrade 2 : mild persistent

indicatedGrade 3 : moderate persistent

not indicatedGrade 4 : severe persistent

Contraindications to immunotherapy

A-General contraindications:(1)-For both sublingual and subcutaneous SIT:

-Serious immuno-pathological and immunodeficiency diseases.-Active cancer ( malignancy which has been controlled for some years

does not represent a contraindication).-Severe psychological disorders.-Treatment with B-blockers in any form.-Severe asthma uncontrolled pharmacotherapy and/or patients

with irreversible airway obstruction (FEV-1 is consistently < 70% pred. after adequate pharmacological treatment.

(2)-Additional contraindications specific to sublingual SIT:-Persistent lesions of the buccal mucosa ulcers , erosions lichen

-Persistent periodontal diseases

Contraindications to immunotherapy

B-Relative contraindications:(1)-For both subcutaneous and sublingual SIT:

-Age: Children < 5 years of age.-Pregnancy is not considered as a contraindication for

the continuation of well tolerated immnunotherapybut treatment should not be initiated during pregnancy.

NB-These relative contraindications do not apply to immunotherapy in case of allergy to Hymenoptera venom , given its potentially life-threatening nature.

Contraindications to immunotherapy

C-Temporary contraindication:(1)-For both subcutaneous and sublingual SIT:

-Unstable asthma.-Any other unstable allergic manifestation ( deterioration

rhinitis , generalized urticaria ,etc).-Vaccination (do not administer immunotherapy on the

same day)(2)-Additional temporary contraindications specific to sublingual SIT:

-Open wound in the mouth.-Recent dental extraction / avulsion / care .-Bloody gingivitis.

Protocols(I)-Protocols with one allergen OR a mixture of related allergens.

SUBLINGUAL IMMUNOTHERAPY (SLIT):

NB –The protocols indicated may be adapted to the reactivity of each individual.

The most common technique is to hold the allergy vaccine under the tongue for 2 minutes and then to swallow it. Patients should note any oral itching, swelling, wheezing, rashes, or esophageal or gastrointestinal distress and discuss it with their physician.

Maintenance treatment for 3 years or longer may be required to achieve adequate long-lasting effects.

(1)-Sublingual Immunotherapy (SLIT):1-Staloral 300>>>Build-Up Phase:Duration 11 days

10 IR/ml 300 IR/ml

>>> Maintenance Phase:Recommended minimal maintenance dose:8 doses (drops) 3 times a week OR 4 doses (drops) every day.

Day 6Day 5Day 4Day 3Day 2Day 1

10 drops8 drops6 drops4 drops2 drops1 dropDose

Day 11Day 10Day 9Day 8Day 7

8 drops6 drops4 drops2 drops1 dropDose

For available standardized allergens: 300 IR/ml

NB- in case of a maintenance dose of 4 doses (drops) every day : stop the build up phase on day 9 and continue directly with the maintenance dose (4 drops) from day 10.

(1)-Sublingual Immunotherapy (SLIT):

2-Staloral>>>Build Up Phase :

Duration 11 days10 IR/ml or IC/ml

100 IR/ml or IC/ml

>>>Maintenance Phase:Repeat the maximum tolerated dose 3 times a week or every

day.

For non-standardized allergens , allergens not available in 300 IR/ml and very reactive patients : 100 IR/ml or IC/ml.

Day 11Day 10Day 9Day 8Day 7

8 drops6 drops4 drops2 drops1 drop Dose

Day 6Day 5Day 4Day 3Day 2Day 1

10 drops8 drops6 drops4 drops2 drops1 dropDose

Stallergens recommendation for Sublingual Immunotherapy:

>>>Build Phase:

Pollens:

-Start if possible 3 to 2 months before the pollen season

>>>Maintenance Phase:

Mites , Animal danders & Moulds:

-Perennial treatment at least during 3 to 5 years

Pollens:-During the pollen season it is normally not necessary to

reduce maintenance dose ;

-Treatment should be maintained during at least 3 to 5 consecutive season .

Pre & co-seasonal protocol for sublingual immunotherapy with Staloral 300 to Pollens

The Protocol indicated may be adapted to the reactivity of each Patient.>>>1st Year:Start the build up phase if possible 2 to 3 months before the pollen season according to the build up phase protocol. Continue the maintenance phase all through the pollen season (2 to 4 months ) and stop at the end of the pollen season.>>>2nd Year:Reinitiate the treatment if possible 2 to 3 months before the pollen season restarting with the dose escalating of the maintenance vial . Then , continue with the maintenance dose all along the pollen season (2 to 3 months) and stop at the end of the season.>>>3rd Year and eventually 4th and 5th Years:Repeat the same protocol as the 2nd year.:

Year 1Start on Day 1: if possible 2 to 3 months before the pollen season

… and all through

the pollen season

Day 11

Day

10

Day 9

Day 8

Day 7

Day 6

Day 5

Day 4

Day 3

Day 2

Day 1

108642110 IR/ml Number of

doses (drops)

8 doses 3 times a

week or 4 doses every day (stop at the end of the pollen

season)

86421300 IR/ml Number of

doses (drops)

Year 2 – Year 3 and eventually Year 4 and Year 5

Start on day 1: if possible 2 to 3 months before the pollen season

… and all through the pollen season

Day 5Day 4

Day 3Day 2Day 1

8 doses 3 time a week or 4 doses every day ( stop at the end of the

pollen season ).

300 IR/mlNumber of doses

(drops)

Subcutaneous Immunotherapy (SCIT)

Phostal – AlustalThe protocols indicated may be adapted to the reactivity of each Patient.

>>>Build-Up Phase:1 injection weekly during 3 to 4 months

>>>Maintenance Phase:The maximum tolerance :The maximum tolerated dose is renewed every 15 days (for 2 months), then every month or more , though the interval between 2 injections must not exceed 6 weeks.General recommended maintenance dose: 1 injection/month of the maximal tolerated dose.

(bottle 3)(bottle 2)(bottle 1)

Stallergenes recommendation for SCIT:

>>>Build-Up Phase:

-In case of Hypersensitivity patients , start the build up regimen with the 0.01 IR/ml or IC/ml concentration (bottle 0).Pollens:-Always start the build up phase at least 4 months before the pollen season.

>>>Maintenance Phase:-The maintenance phase must be sustained for at least 3 to 5 years.-The interval between 2 maintenance injections must not exceed 6 weeks;-For safety reasons , when starting a new maintenance vial : inject only half of the usual maintenance dose and , if well tolerated , revert to the full maintenance dose for the next injection.Pollens:-During the pollen season: inject only half of the usual maintenance dose and revert to the full maintenance dose at the end of the pollen season.

Protocols with Unrelated Allergens

1-Suligual Route:

2-Subcutaneous Route:

In case of 2 simultaneous SIT course by subcutaneous route , and in order to be able to determine which treatment is in case in the event of an adverse reaction , we recommend :

-to inject the 2 treatments in the 2 different arms;

-to wait at least for 30 minutes between the 2 injections.

Switch Protocols

1-From Subcutaneous route to Sublingual route:

2-From Sublingual route to Subcutaneous route:

Safety aspects and Patient follow-up

Safety Aspect:1-Sublingual ImmunotherapySide effects: undesirable effects are rare but may nevertheless signal a need for caution.A-Local reactions: these reactions are common and mainly observed during the build-up phase.-Pruritus in the mouth and/or on the lips;-A burning feeling around the mouth and lips;-Lips or sublingual oedema;-Gastrointestinal , abdominal pain and diarrhea.B-Systemic reactions :-Rhinoconjunctivitis;-Asthma. Both the frequency and the characteristics of side

effects are the same in children and adults.

What to do in case of adverse reaction?

In case of mild local reaction:-for a unique episode with spontaneous improvement: continue with no change; -for repeated episodes: return to the previous well tolerated dose then increase day after day until the full dose.In case of mild to moderate local and systemic reactions:-Step back to the previous well tolerated dose for 2 days , then resume the stepping up procedure.In case of severe local and systemic reactions:-Suspend administration for 48 hours;-If the symptoms regress after discontinuation , resume administration at half the last dose and recommence the step-up procedure;-If the symptoms fail to regress even once the treatment has been discontinued , investigate possible alternative causes because it is unlikely that it is the SIT that is responsible for the reaction . Resume SIT.

NB: In the event of pruriginous manifestations , prescribe an antihitamine.

Subcutaneous Immunotherapy

-International recommendations together with Good Medical Practices guidelines stipulate that injection of the allergen extract should be carried out by a PHYSICIAN or by a NURSE under the supervision of a PHYSICIAN. -There should always be an EMERGENCY KIT on the hand.-Equipment recommended for settings where subcutaneous immunotherapy is administered:

1-Injectable adrenaline .HCl 1 mg/ml;2-Equipment for administering oxygen;3-Equipment for administering intravenous fluids4-Antihistamines : oral and for injection;5-Oral or intravenous corticosteroids.

Good clinical practicesA-Before the injection-Check the emergency kit;-Check the patient’s condition: inquire about:

.Any reaction that might have followed the last injection;

.Any event that might be relevant (infection or an asthma attack or an exacerbation of allergic symptoms);

.Any drugs taken in the interval . Patients taking B-blockers (including local treatment) should not receive immunotherapy;

.Check that PEFR readings is > 80% of “personal best” for patients with asthma.-Check the vial:

.Correct allergen composition, concentration and expired date;

.Check the dose to be administered by comparing it to previous dose and the dosage schedule.

Good clinical practices

B-The injection itself:-Check the interval since last injection,-Use a disposable 1 ml syringe (with 1/100 graduations)-Shake the vial and using regular aseptic technique , aspirate the exact volume to be administered ;-Administration by strict deep subcutaneous route in the lower deltoid region of the arm or in the upper thigh . Always draw back on the syringe to ensure that needle has not entered a blood vessel.

C-After the injection:-Keep the patient under medical observation for 30 minutes after the injection : A longer waiting period is necessary for high-risk patients(e.g. high degree of hypersensitivity);-The injection site has to be inspected before the patient leaves the doctor’s office/clinic;-Advice the patient to avoid strenuous exercise , hot baths and sauna for the rest of the day;-Advice the patient to consult the physician or call for emergency assistance in case of severe delayed reaction.

Good clinical practices

NB: The maintenance phase appears to associated with fewer systemic reactions than the build-up phase.

D-Most current risks with the use of subcutaneous immunotherapy:-Errors in dosage;-Presence of symptomatic asthma;-High degree of hypersensitivity;-Injections from new vials ;-Injections made during periods of exacerbation of symptoms.

E-When postpone an injection?(refer to temporary contraindications)

-In case of intercurrent disease: Treat the symptoms and make the SIT injection after recovery.

-In case of vaccination: Vaccinations against infectious diseases should be scheduled on a different day than SIT injections.

Side effects of Subcutaneous immunotherapy

A-Local reactions:

-Local reactions occur at the injection site:

.Flare and edema;

.Subcutaneous nodules (only for extracts on Aluminium Hyroxide).

They can be divided into reactions that occur within 20-30 min. and those that occur later than 30 min. after the injection. Local reactions can cause patient discomfort.

Side effects of Subcutaneous immunotherapy

B-Systemic reactions:-Systemic reactions are characterized by generalized signs and /or symptoms occurring away from the injection site . Such reactions usually begin within a few minutes after the injection and more rarely after 30 min.

EAACI grading :1)-Non-specific reactions:

Reaction probably not IgE-mediated; i.e.discomfort, headache, arthralgia, etc.

2)-Mild systemic reactions:Mild rhinitis and/or asthma (PEFR > 60% of expected or personal best values )

responding adequately to antihistamines or inhaled B2-agonist.

3)-Non-life-threatening systemic reactions:Urticaria, angiodema, or severe asthma (PEFR < 60% of expected or of personal best

values) responding well to treatment.

4)-Anaphylaxis shock:Rapidly evoked reaction of itching, flushing, erythema, bronchial obstruction,

hypotension, etc. requiring intensive treatment.

What to do in case of an adverse reactions?

What about SIT continuationTreatment of the adverse reaction

Type of reaction

Continue SIT without any change.Apply an ice-bag on the local reaction

Small local reactions (diameter < 5 cm in adults or < to 3 cm in children)

Reactions at the site of the injection

Build-up phase :-For the next injection repeat the

previous well tolerated dose , and if there is no adverse reaction, continue the dose escalation for the next injections.

Maintenance phase : -For the next injection : inject only half of the usual maintenance dose, and if well tolerated , revert to the full maintenanance dose for the next injections

Edema and urticaria : -Oral corticosteroid: 2 mg/kg up to 60 mg / day for 2 or 3 days.--Oral H1-Antihistamines.

Large local reactions (diameter =/> 5 cm in adults or =/> to 3 cm in children)

Reaction at the site of the injection

What to do in case of an adverse reactions?

What about SIT continuation

Treatment of the adverse reactionType of reaction

Build-up phase:-Control the symptoms .-For the next injection : repeat the previous well tolerated dose, and if there is no adverse reaction , continue the dose escalation for the next

injection.Maintenance phase:-Control the symptoms.-For the next injection : inject only half of the usual mainatenance dose , and if well tolerated revert to the full maintenace dose for the next injections.

Moderate rhinitis/moderate urticaria:-Oral steroids: 2 mg/kg up to 60 mg /day for 2 or 3 days;

-H1-Antihistamines.

Moderate asthma : (Bronchospasm or drop =/> 20% in the predictive PEFR associated or not with coughing or respiratory distress):-2puffs of short-acting B2-agonist (to be repeated after 5-10 min.-Or nebulization of B-agonist (salbutamol at dose of 0.02 ml/kg of 0.5% solution or one vial of terbutaline.

Moderate systemic reactions

Reactions away from the site of the injection

What to do in case of an adverse reactions?

What about SIT continuation

Treatment of the adverse reactionType of reaction

-Treat the reaction and make sure that symptoms have totally disapeared.-Doctors should consider whether to continue subcutaneous SIT with lower doses or to stop it;-In case of stop , to propose to the patient a sublingual form of SIT , if available.

Severe urticaria / angioedema:-Oral steroids: 2mg/kg up to 60mg /day forv 2 or 3 days.-H1-Ahistamines.

Severe asthma:-Nebulisation of B2-agonist (salbutamol at dose of 0.02ml/kg of 0.5% solution or one vial of terbutaline);-Or 14 puffs of short –acting B2-agonist (to be repeated after 5-10 min.-Mehtylprednisolone : 2mg/kg iv ; -Nasal oxygen.

Severe systemic reactions

Reactions away from the site of the injection

What to do in case of an adverse reactions?

What about SIT continuation

Treatment of the adverse reactionType of reaction

-Stop subcutaneous SIT.-Doctors could consider whether or not to propose to the patient to follow his/her treatment with sublingual form of SIT , if available.

Generalised reaction ( urticaria + asthma + larygeal edema + drop in BP ):-Lay the patient down on his/her back with legs in the air , or on his/her side (the safety position in case of vomiting).-Adernaline IM : 0.01 mg/kg which can be repeated after 15 to 30 min (weight < 20 kg -- dose 0.15 mg / weight > 20 kg -- dose 0.30 mg / 2 doses of 0.30 mg in heavy subjects , i.e. 75-80 kg).-Nasal oxygen .-IV antihistamines , -Methylprednisolone : 2 mg/kg IV ,-IV fluids if the patient is hypotension,.

NB-CALL for EMERGENCY assistance.

Anaphylactic shock

Reactions away from the site of the injection

Recommendations for patient’s follow-up frequency

The doctor is the only person able to define the optimal follow-up frequency to his/her patient’s profile.

>>> Sublingual immunotherapy:A-For a perennial protocol:To reach a good patient’s compliance , it is recommend seeing the patient every 3 months during the 1st year of treatment and every 4 to 6 months during the following years of treatment.

B-For pre and co seasonal protocol:To reach good patient’s compliance it is recommend seeing the patient 3 time/year during all the years of the treatment , according to the following scheme:

-6 to 4 months before the season , visit for prescription ;-1 month after the beginning of the treatment: visit to evaluate safety

and compliance.-6 months after beginning of the treatment: follow-up visit.

Recommendations for patient’s follow-up frequency

>>>Subcutaneous immunotherapy:

A-Initial phase:

Visit at the doctor’s office each week for weekly initial injection.

B-Maintenance phase:

Visit at the doctor’s office once a month for maintenance injection.

NB: It is generally recommended that the antigen dose be reduced by 50% when a new vial is begun.

Treatment interruptionSublingualSubcutaneousInterruptionPhase

Continue the dose escalation without

any change.

Repeat the previous dose and continue the build-up

phase.

1 – 2 weeksBuild-up phase

Repeat the previous dose, then continue phase the build-up

Step back to 0.1 ml (1st dose) with the same concentration,

then continue the build-up phase .

2 weeks to1 month

Restart the dose escalation with the

same vial and continue the build-

up phase.

Restart the dose escalation with the 10-fold less

concentration vial (go back to previous concentration) and continue the build-up phase.

> 1 month

Treatment interruption

SublingualSubcutaneousInterruptionPhase

No change in the dosage and

concentration

No change in the dosage and concentration

< 1.5 monthsMaintenance phase

Reduce the dose by 50% , then continue with the previous well tolerated dose .

Restart with the build-upphase from 0.1ml (1st dose) of 1 IR or IC/ml (bottle 2) vial till the maintenance dose and then continue the treatment .

1.5 months to 6 months

(1)-Sublingual Immunotherapy (SLIT):

>>> Maintenance Phase:

Recommended minimal maintenance dose:

8 doses (drops) 3 times a week OR

4 doses (drops) every day

NB- in case of a maintenance dose of 4 doses (drops) every day : stop the build up phase on day 9 and continue directly with the maintenance dose (4 drops) from day 10.

Thank You

What is Cluster Immunotherapy?

At each session, the patient will receive

2-3 doses of immunotherapy separated by a

30 minute waiting period. While sessions

may last up to 90 minutes, a patient can

reach maintenance dosages in a little as 4

weeks. Such a schedule is very appealing to

patients desiring to see results quicker or

whose schedule is better suited to a more

intensive initial phase of immunotherapy.

Rush and Cluster Immunotherapy

Consent for accelerated schedules

When an accelerated schedule is used then

additional informed consent should be obtained

in which the additional procedures, risks and

benefits are disclosed.

This may be obtained using a separate

consent form designed for accelerated

immunotherapy in addition to a form designed

for weekly immunotherapy.

Cluster immunotherapy (rapid desensitization)

Pre-medication is required for cluster

immunotherapy 2 hours prior to the injection(s)

typically with:

-specific antihistamines,

-leukotriene modifiers or more depending upon

each individual case.

A typical cluster immunotherapy schedule at

Allergy & Asthma Care is as follows

It is strongly suggested that all patients on allergy injections have an epinephrine auto-injector (EpiPen) with them and show the nurses before the shot can be given.

Cluster Immunotherapy

-With cluster immunotherapy, 2 or more injections are administered per visit to achieve a maintenance dose more rapidly than with conventional schedules.

-Cluster schedules are designed to accelerate the buildup phase of immunotherapy. -Cluster immunotherapy usually is characterized by visits for administration of allergen immunotherapy extract 1 or 2 times per week with a schedule that contains fewer total injections than are used with conventional immunotherapy. With cluster immunotherapy, 2 or more injections are given per visit on nonconsecutive days.

-The injections are typically given at 30-minute intervals, but longer intervals have also been used in some protocols. This schedule can permit a patient to reach a maintenance dose in as brief a period of time as 4 weeks. -The cluster schedule is associated with the same or a slightly increased frequency of systemic reactions compared with immunotherapy administered with more conventional schedules. -The occurrence of both local and systemic reactions to cluster immunotherapy can be reduced with administration of an antihistamine 2 hours before dosing.

What are the Risks of Cluster Immunotherapy?

As with any change, however, there can be some drawbacks. With such rapid escalation in dosing, there can be an increase rate of local reactions. To combat this, Allergy Partners recommends pre-medication with a non-sedating antihistamine and a leukotriene modifier.

In addition, Cluster may not be suited for extremely sensitive patients or those with significant asthma or underlying medical conditions. Some providers may choose a slightly modified schedule based on your history, symptoms, and test results . As always, your Allergy Partners physician will discuss the relative risks and merits of Cluster with you to ensure that you receive immunotherapy in the manner best suited to your individual situation.