Immunotherapy

Literature Reading
Desno Marbun
Pembimbing : dr Melati Sudiro, MKes, Sp THT-KL(K)
Faculty of Medicine Padjadjaran University
Dr. Hasan Sadikin General Hospital
Bandung
2014
History of Allergen Immunotherapy
During last 100 years : Emergence of an affective solution
allergen immunotherapy

Development in several contrasting periods :

Beginnings 1911
1950- 1980
The renewal of AIT with SLIT ( 1980 )
Acceleration and recognition in the last 10 years

Credible and EMA approved : a new therapeutic class for

severe allergic rhinitis patient

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 History of Allergen Immunotherapy
1911 : The quest begins
Leonard Noon and John Freeman : the
founders
Showed efficacy of allergen
immunotherapy in seasonal allergic
rhinitis
-Patient injected with increasing doses
of pollen extract

3
 Developments between 1911 and
1950
Greater understanding of mechanisms involved

The concept of blocking antibodies

Robert Cooke linked allergic rhinitis and asthma (1918)
Emergence of desensitization (1920s)
Prausnitz and Kustner Serum transfers transferred sensitivity

Clinical testing of subcutaneous formulations

Vander Veer, Cooke, Black expanding patient populations in
both studies
and in general practice, but emergence of anaphylaxis (1930s)

First controlled study of immunotherapy in allergic

rhinitis
Efficacy testing under controlled conditions but with
substandard preparations (1949) 4
 The dark ages: 1950s 1980s
Allergen immunotherapy is sidelined

Subcutaneous immunotherapy haunted by

anaphylaxis
Reports of fatalities discouraged use of AIT efficacy needs
to be balanced against risk
Researchers looked for safer administration routes and
improved preparations

Exploration of extract quality as cause of side effects

Early placebo controlled study, Frankland and Augustin
(1954)
Efficacy surprisingly high, but negative perception of AIT
because greater purification did not resolve side effects

5
 1950 1980

Allergen immunotherapy shown to be

effective
but limited by:
- Risk of anaphylaxis with subcutaneous
formulations
- Conflicting results from clinical studies
- Poorly designed clinical studies
- No standardization of manufacturing
processes or formulations
- Too many questions left unanswered
6
 1980 2000: The renewal of AIT

The reasons for the resurgence in interest:

Increasing prevalence of allergic rhinitis
By 2000 allergy prevalence had risen to 25-30%

Greater recognition of the disease burden

Allergic rhinitis no longer regarded as a trivial disease
Recognition of consequences on sleep, quality of life, performance
RQLQ questionnaire (1991)

Greater patient expectations

Effective symptomatic treatment had changed patient expectations
Patients expected effective relief, even a cure

Emergence of sublingual immunotherapy

Safer and easier administration

7
Definition
Allergen Immunotherapy
Repeated administration of specific
allergens to patients with IgE-mediated
conditions for the purpose of providing
protection against the allergic
symptoms
and inflammatory reactions associated
with natural exposure to these
allergens.
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 IMMUNOLOGIC RESPONSES TO
IMMUNOTHERAPY

1. Decreases in the sensitivity of end

organs.
2. Changes in the humoral and
cellular responses to administered
allergens.
3. Decreased early and late
responses.
4.Decreased allergen-induced
eosinophil, 9
 IMMUNOLOGIC RESPONSES TO
IMMUNOTHERAPY

Shortly after initiation of immunotherapy, increase in

CD4, CD25 regulatory T, lymphocytes secreting IL-10
and TGF- in allergen-specific T-cell responsiveness.

Deviation from TH2 to TH1 cytokine response to the

administered allergen predominates.

Specific IgE levels initially increase and then gradually

decrease.

Levels of specific IgG1, IgG4, and IgA increase.

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IMMUNOLOGIC RESPONSES TO
IMMUNOTHERAPY

J ALLERGY CLIN IMMUNOL

JANUARY 2011 11
J ALLERGY CLIN IMMUNOL
JANUARY 2011
12
J ALLERGY CLIN IMMUNOL
JANUARY 2011

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Clin Transl Allergy 2012 ; 2 : 2

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IMMUNOLOGIC RESPONSES TO
IMMUNOTHERAPY

Immune regulation during the time course of allergen-SIT.

Specific immune responses are observed during the course of allergen-SIT.
1.An early desensitization effect including decrease in mast cell and basophil
degranulation soon after
the first administration of allergens.
2. Generation of allergen-specific Treg cells and suppression of effector cells.
3. An early increase and a late decrease in specific IgE levels.
4. A relatively early increase in specific IgG.
5. A late decrease in type I skin test reactivity.
6. A decrease in tissue mast cell and eosinophil numbers and a release of their mediators
after a few months.
Clin Transl Allergy 2012 ; 2 : 2 15
 Indication
1. Patients with allergic rhinitis, allergic
conjunctivitis, or asthma.
2. Atopic dermatitis ( if associated with aeroallergen
sensitivity ).
3. Patient with reaction to hymenoptera sting
( history of systemic reaction especially
associated with respiratory symptoms ,
cardiovascular symptoms and relevant specific Ig
E antibodies ).
4. History of systemic reaction to imported fire ant
and clinically relevant specific Ig E antibodies.
5. Patients have frequent and disabling large local
reactions. 16
Contraindication
1. Negative test results for specific IgE
antibodies.

2. Positive test results for specific IgE antibodies

that do not correlate with suspected triggers,
clinical symptoms, or exposure.

3. Mentally or physically unable to communicate

clearly with the physician and patients have
history of noncompliance.

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 Precautions
Exposure to adrenergic blocking agent is a risk factor for
more serious and treatment resistant anaphylaxis.

ACE inhibitor have been associated with greater risk for

more severe reaction from venom immunotherapy

Not be initiated unless the patients asthma is stable with

pharmacotherapy.

Patients with severe or uncontrolled asthma are increased

risk for systemic reactions
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 SPECIAL CONSIDERATIONS IN IMMUNOTHERAPY

- Effective and well tolerated.

Children
- Can be initiated less than 5
years based on severity,
risk/benefit ratios.

- In children with allergic rhinitis ,

might prevent asthma.

- There several reports of efficacy and

safety in children as young as 3 to 16
years old.

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SPECIAL CONSIDERATIONS IN IMMUNOTHERAPY

- Can be continued but is usually

not
initiated.

- If pregnancy occurs during the Pregnancy

build-up phase discontinuation

of
immunotherapy should
considered.
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 Immunodeficiensy and autoimmune
disorders
- Can be considered in patients with
immunodeficiency early to middle HIV

disease, no history opportunistic and

history no plasma HIV viremia.

- Peripheral CD4 count of 400 or

more cells/mL .

- That reported induced a transient T cell

proliferation and increase RNA viral
load with resolved with highly active
retroviral therapy.
SPECIAL CONSIDERATIONS IN
IMMUNOTHERAPY
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 SPECIAL CONSIDERATIONS IN
IMMUNOTHERAPY
geriatric
No absolute upper age limit for
initiation of immunotherapy.

Some patients might be taking

medications that could make treatment
of anaphylaxis with epinephrine more
difficult, such as Blocker.

Have significant co morbid medical

conditions such as hypertension,
coronary artery disease,
cerebrovascular disease , and cardiac
arrhythmias.

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IMMUNOTHERAPY SCHEDULES

Conventional
schedules
The The dose and concentration of
allergen immunotherapy extract
build-up are increase.
1-3 times per week.
phase 3-6 months

The patient receives an effective

Maintenan therapeutic dose over a period of
time.
ce phase Interval can be progressively
increase , as tolerated up to an
interval of 4 weeks
23
 Cluster schedules

Designed to accelerate the build-up phase of

immunotherapy.

2 or more injections are administered per visit to

achieve a maintenance dose more rapidly than with
conventional schedules.

The injections are typically given at 30-minute intervals.

Increased frequency of systemic reactions.

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 Rush schedules

Achieve a maintenance dose more quickly than

weekly schedules.

That permitted patient to achieve a maintenance

dose in 6 days.

Patients were required to remain in the hospital.

Increased risk local and systemic reactions.

(15-100 % of premedicated patients )

25
Dose adjustments for
late injections
No evidence based guideline on
dose adjustments for missed
immunotherapy doses.

The author noted that a stepwise

reduction (with the late interval
beginning with the date of the
missed doses) beginning at 3
weeks late for build up ( reduce 1
dose per week late)
26
 Adverse reactions
Local reactions.
Large local reactions (LLRs) If
larger than
the patients palm

Local reactions not predictive

systemic reactions.
Local reactions not predictive local
reactions at next injection.
27
 Adverse reactions
Systemic reactions.

Most serious systemic reactions from allergen

immunotherapy occur within 30 minutes after
injection.

Delayed systemic reactions occurring after the 30-

minute wait period in general not severe.

Biphasic immunotherapy reactions if resolution of

the initial reaction with recurrence at 2 to 24 hours.

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 World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction
Grading System

Grade 1 Grade 2 Grade 3 Grade 4 Grade

5
Symptom(s)/sign(s) of one organ Symptom(s)/sign(s) of more Lower respirator Lower or Upper
system present than one organ system respiratory
Cutaneous present Asthma (e.g 40% PEF or
FEV 1 drop, NOT
Generalized pruritus, urticaria, flushing Or responding to an inhaled Respiratory failure Death
or sensation of heat or warmth bronchodilator) with or without loss
Or Lower respiratory of consciousness
Or
Angioedema (not laryngeal, tongue or Asthma: cough, wheezing, Or
uvular) shortness of breath (e.g less Upper respiratory
than 40% PEF or FEV 1 drop, Cardiovascular
Or responding to an inhaled Laryngeal, uvula or
bronchodilator) tongue edema with or Hypotension with or
Upper respiratory witout stridor without loss of
Or consciousness
Rhinitis(e.g sneezing, rhinorrhea, nasal
pruritus and/or nasal congestion Gastrointestinal

Or Abdominal crampls, vomiting

or diarrhea
Throat-clearing (itchy throat)
Or
Or
Other
Cough perceived to come from the
upper airway, not the lung, larynx, or Urine cramps
trachea

Or

Conjunctival
29
Conjunctival erythema, pruritus or
tearing

Other
 Recommended equipment and
medications to treat anaphylaxis
Adequate equipment and medications should be immediately
available to treat anaphylaxis, should it occur. This should
include at
least the following equipment and medications:
Stethoscope and sphygmomanometer
Tourniquet, syringes, hypodermic needles, and large-bore needles(14-
gauge)
Aqueous epinephrine HCL 1:1000wt/vol
Equipment to administer oxygen by mask
Intravenous fluid set-up
Antihistamine for injection (second-line agents for anaphylaxis , but H1
and H2 antihistamines work better together than ether one alone).
Corticosteroids for intravenous injection
Vasopressor
Equipment to maintain an airway appropriate for the supervising
physicians expertise and skill. 30
Glukagon kit available for patient receiving blocker
 Management of immunotherapy-
induced systemic reactions
The first line treatment is epinephrine.
No Contraindication to epinephrine
administration in patients with anaphylaxis.
Delayed administration epinephrine
fatalities.
Epinephrine 1 : 1000 dilution 0,2-0,5 ml
should be administered every 5 minutes
(0,01 mg/kg max 0,3 mg/ dose in
children.

31
 Premedication reduce
local and systemic reactions

Antihistamine
Decreased LLRs and cutaneous symptoms of pruritus,
urticaria, and angioedema but not decrease respiratory,
gastrointestinal, or cardiovascular reactions.

Montelukast
Decreases the size of local reactions rush VIT.

Omalizumab
Improve the safety and tolerability of cluster and rush
immunotherapy schedules in patients with moderate
persistent asthma and allergic rhinitis.

Combination pretreatment (ketotifen,

methylprednisolone , theophylline) used during rush
treatment decreased the systemic reactions. 32
 Measures of efficacy
- Subjective :
Reduction medication require to control
symptom
scoring system for measuring symptoms
( 0 = absent , 3 = severe)

- Objective :
Increase in allergen Spesific IgG
33
 Injection Technique

Use upper outer surface of arm

Ensure sterile technique
Use 1ml syringe and orange needle
Inject at 45 by deep subcutaneous route
Record any local/systemic reaction
Administration of
Immunotherapy
 Noninjection Routes of
Immunotherapy

Intranasal, Sublingual, oral,

intralymphatic,
epicutaneous.

There are no FDA approved formulations

for a noninjection immunotherapy.

36
 Noninjection Routes of
Immunotherapy
Sublingual Immunotherapy
Indication :
- Inhalant allergens
- Ragweed and grass pollen
Adverse reactions
- local reactions : oral pruritus,
edema of the mouth

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 Non-Injection or Local Routes -
1

Oral immunotherapy (OIT): allergen

immediately swallowed, as drops, tablets
or capsules.

Sublingual immunotherapy (SLIT):

allergen kept under the tongue for 1-2
minutes, then swallowed (the sublingual-
spit mode is no longer in use).
Methods of immunotherapy
Oral IT (OIT)
swallowed with food
open and blinded studies
mg gms of food
 Non-Injection or Local Routes -
2

Local nasal (LNIT): allergen

sprayed into the nostrils as aqueous
solution or dry powder.

Local bronchial (LBIT): allergen

inhaled with a deep inspiration.
 Non-Injection or Local
Routes
Bronchial and oral route are not recommended
for clinical use, due to insufficient demonstration
of efficacy and the occurrence of side effects.

Nasal IT (LNIT) and Sublingual IT (SLIT): Based

on the available literature, local nasal
immunotherapy and sublingual immunotherapy
can be considered as viable alternatives to
subcutaneous administration.

WHO Position Paper 1998

 NOVEL FORMULATIONS: ALLERGOIDS AND ADJUVANTS

Allergoids are modified allergen

extracts processed in a way that
reduces the extracts allergenicity
while preserving its antigenicity.

There are no FDA-approved allergoids

in the United States.

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NOVEL FORMULATIONS: ALLERGOIDS AND ADJUVANTS

Adjuvants might enhance the effectiveness of allergen

immunotherapy by shifting the immune response toward
TH1 production.

The 2 adjuvants most extensively studied with allergen

immunotherapy are an immunostimulatory oligonucleotide
sequence of DNA containing a CpG motif (CpG) and 3-
deacylated monophospholipid A (MPL).

Clinical trials with these adjuvants, in combination with

ragweed (CPG and MPL) and grasses (MPL), demonstrate
significant improvement in allergic rhinitis symptoms with 4
to 6 injections administered preseasonally.

Neither of these adjuvants are available as FDA-approved

allergen extracts.
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12 STEPS ALGORITHM FOR ALLERGEN
IMMUNOTHERAPY
Patient presents with allergic rhinitis, allergic conjunctivitis, allergic asthma or
insect allergic

Evidence of
specificNO
IgE
antibodies. Test Not a candidate for
result correlate immunotherapy
with clinical
symptoms and 3
exposure? 2
YES

Assess
Risks, benefits and costs of appropriate management options
Immunotherapy
Allergen exposure reduction
Medications
Patient preferences
Response to prior treatment
Severity of disease
4
 12 STEPS ALGORITHM FOR ALLERGEN
IMMUNOTHERAPY (CONT)
Is
immunotherapy Immunotherapy not
recommended
given
NO
for this patient? 6
5

Obtain informed consent

Counsel and educate patient about the benefits and
risks of
immunotherapy including anticipated duration and
onset of
efficacy 7 YES

Identify
Specific allergenic extracts
Starting dose and immunotherapy schedule
Maintenance concentrate

8
 12 STEPS ALGORITHM FOR ALLERGEN
IMMUNOTHERAPY (CONT)
Administer Immunotherapy
Safety equipment and procedures in places
Medical personal appropriately trained to identify
and treat immunotherapy reaction.
At least 30 minutes wait in office after injection
9
Manage Reaction
Re Assess risk/ benefit
immunotherapy
Reactions to
Consider dose/schedule
immunotherap
adjustment
y injections? Consider discontinuing
10 Yes immunotherapy
11

NO
Follow up every 6 to 12 months while on immunotherapy or
more frequently for evaluation/management of
immunotherapy reactions and/or underlying allergic disease
or co-morbid conditions

Assess follow up

Clinical response to immunotherapy ( e.g, symptoms, medication

use)
Immunotherapy schedule, reactions, compliance
Continuation of immunotherapy treatment
12
 FUTURE TRENDS IN IMMUNOTHERAPY

Novel routes for more effective, more convenient, and

safer allergen immunotherapy are being investigated
throughout the world :oral, sublingual-swallow, or nasal
routes
Preformed soluble antigen-antibody complexes have been
shown effective in patients with house-dust mite allergy,
but whether they will be clinically feasible is controversial.
The uses of immunogenic but nonallergic overlapping
synthetic peptides (short and long) and large recombinant
allergen peptide fragments are being explored on an
experimental. Some of this benefit is attributable to
nonspecific immunostimulatory oligodeoxynucleotides
(CpG, cytosine phosphate guanine) with tolerizing motifs.
47
 Humanized anti-IgE monoclonal antibody has
already been shown to have modest clinical
effects in both allergic rhinitis and
asthmarapid rush forms of immunotherapy.
Cytokine and cytokine receptor modulation
are active areas of current clinical research.
The most promising candidates are
monoclonal anti-interleukin (IL)-5 and anti-IL-
13 antibodies, but antagonists to IL-4 (ie,
soluble IL-4 receptor ) are also promising
treatments.
48
 KEY HIGHLIGHTS OF THE UPDATE
New indications for allergen immunotherapy
- Atopic dermatitis in subjects with
aeroallergen sensitization.

Clinical studies to date do not support the use of

allergen immunotherapy for food
hypersensitivity,chronic urticaria, or angioedema.
Therefore,allergen immunotherapy for patients with
these conditions is not recommended.

Measurement of baseline tryptase is recommended in patients

with moderate or severe anaphylactic reactions to stings.
Increase serum tryptase associated with systemic reactions.

49
 KEY HIGHLIGHTS OF THE UPDATE

Patient age and initiation of allergen

immunotherapy

- Pediatrics: There is no specific lower limit for

immunotherapy if indications are present .

- Elderly population : Risk/benefit assessment be

carefully evaluated because they might have
co morbid medical conditions that could
increase immunotherapy risk.
50
 KEY HIGHLIGHTS OF THE UPDATE

Pregnancy :
- Allergen immunotherapy can be
continued
but usually is not initiated

- Discontinuation therapy should be

considered if occurs during the build-
up
phase. 51
 KEY HIGHLIGHTS OF THE UPDATE

Patients with HIV infection

Discussion of the published literature
and case reports on patients with HIV
and allergen immunotherapy.

Local reactions and systemic reactions.

Counseled on possibility of immediate
and delayed systemic reactions
52
 KEY HIGHLIGHTS OF THE UPDATE

Blocker medication and angiotensin

converting enzyme ( ACE ) inhibitor
medications.

Premedication and immunotherapy.

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THANK YOU

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