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 jg
from 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)

-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.

-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 Planning
Choosing 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
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 schedules
While 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 schedules
There a number of advantages and disadvantages to using an
accelerated immunotherapy schedule:
Advantages
May 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
Disadvantages
There 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 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
0
0.5
1
0
0.5
1
1
2
1
0
0.5
1
0
1
1
2
2
O
1
13
0
1
14
0
1
15
16
17-10
4 weekseverythen

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
0.1
1
10
20
30
40
0
0.5
1
1.5
2.5
3.5
1
50
50
0
1
15
10043
10071
10099
Maintenance dose reached in 6 weeks then every 4 weeks

Rush
Dose in microgram
HourDay
o.o1
0.1
1
2
0
0.5
1
2.5
1
4
8
1o
20
0
1
2
3
2
40
60
80
0
1
2
3
1004
1008
10015
10029
10043
10071
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
0.001
0,01
0.1
0
0.5
1
1
1
5
10
0
1
2
8
20
30
1
2
15
50
50
1
2
22
10029
10036
10064
10092
Maintenance dose reached in 4 weeks, then
every 4 weeks

Conventional
dose in micrograms
HourDay
0.01
0.1
0
0.5
1
1
2
0
1
8
4
8
0
1
15
10
20
0
1
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.

Allergens for immunotherapy
Already validated by control studies
Specific immunotherapy
Grasses
Trees
Weeds
Pollens
D. Pteronysinus
D. Farinae
Storage mites
Biomia
Mites
Cat
Dog
Epithelia
Alternaria
Cladosporium
Moulds

Recommendations for allergen mixtures
Allergen mixtures
MouldsEpitheliaMitesPollensAllergens
NoNoNoYesPollens
NoNoYesNoMites
NoYesNoNoEpithelia
YesNoNoNoMoulds
No-Unrelated allergens mixture not recommended by WHO
Yes-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
Sublingual 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
Sublingual 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

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 immnunotherapy
but 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.

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.

2-Staloral
>>>Build Up Phase :
Duration 11 days
10 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 dropDose
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
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 1
Start on Day 1: if possible 2 to 3 months before the pollen season
… and all
through
the pollen
season
Day
11
Da
y
10
Day
9
Da
y 8
Day
7
Da
y 6
Day
5
Da
y 4
Day
3
Da
y 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/ml
Number of doses
(drops)

Subcutaneous Immunotherapy (SCIT)
Phostal – Alustal
The protocols indicated may be adapted to the reactivity of each Patient.
>>>Build-Up Phase:
1 injection weekly during 3 to 4 months
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.
-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 Immunotherapy
Side 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 fluids
4-Antihistamines : oral and for injection;
5-Oral or intravenous corticosteroids.

Good clinical practices
A-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.

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.

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 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 about SIT
continuation
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 about SIT
continuation
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 interruption
SublingualSubcutaneousInterruptionPhase
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 to
1 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-up
phase 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

>>> 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.

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.

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.

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