by Dr. Khairul Hassan Jessy MD (Chest Diseases) Associate Professor, Respiratory Medicine National Institute of Diseases of the Chest and Hospital (NIDCH) Mohakhali, Dhaka.

1. Dr. Khairul Hassan Jessy
MD (Chest Diseases)
Associate Professor, Respiratory Medicine
National Institute of Diseases of the Chest and Hospital (NIDCH)
Mohakhali, Dhaka.
Role of Immunotherapy in
Bronchial Asthma & Allergic
Rhinitis

4. CASE STUDY 1
 Mrs. Jesmin, 40 years old service holder, is
suffering from asthma for the past 20 years
and needs medicine daily for her asthma (Step
IVb).
 Her daily requirement used to be symptom
free with inhaled corticosteroids 1000
microgram of Fluticasone with LABA.
 She is now frequently having Asthma episodes
with occasional night attacks, eye congestion
and rhinorroea.
 She is now frequenly missing the office and
visiting doctor’s chamber for her asthma.
 She is looking for anything new that can be
tried.

5. CASE STUDY 2
 Mr. Kabir, A busy 28-year-old professional,
consults his physician for advice on long-
standing Allergic Rhinitis.
 He reports having itchy eyes and an itchy
nose, lacrimation, sneezing, rhinorrhoea, and
nasal congestion during the summer months.
 In previous years, he tried various
antihistamines and nasal sprays, but these
treatments only had limited benefit.
 A friend has suggested a corticosteroid
injection or allergy injections, but he is
hesitant to receive corticosteroids and unable
to give up the time from work to receive
injections.
 He is evaluated by an allergist.
 Skin testing confirms that he is strongly
sensitized to house-dust mites, with modest
reactions to cat dander and grass pollen.

6. What are the
investigations planned
for their allergy?
What will be planned
to give them?

7. What are the investigations planned for
their allergy?
Ans: Allergy test or Specific IgE
What will be planned to give them?
Ans: Immunotherapy

8. CASE STUDY 3
 Mrs. Kolpona 35 years is suffering from
asthma for the past 20 years and needs
medicine daily for her asthma (GINA 4b)
 Her daily requirement to be symptom free -
inhaled corticosteroids 1000 microgram of
Fluticasone with LABA.
 She has recently developed joint pains and
swellings and has early morning stiffness.
 Will you give her immunotherapy?
ans: Investigate for Rheumatoid
arthritis – Collagen Vascular disease is
a contraindication

9. CASE STUDY 4
 Mr. Kashem, 24 years University student,
consults his physician for advice on his
Bronchial asthma for the last 12 years.
 His mother and maternal uncle are asthmatic.
 He reports having asthma attacks both in
summer months as well as winter.
 He occasionlly suffers from itchy eyes with
lacrimation, itchy nose, sneezing, rhinorrhoea,
and nasal congestion specially during the
summer months.
 He is using Bronchodilator as well as Steroid
inhalers for the last 5-7 years, with sometimes
oral prednisolone tablets during acute attacks.
 He wants to know from his Pulmonologist
whether he should continue his medications
lifelong and whether any cure of asthma
available.

10. CASE STUDY 4
Doctor, is there any chance of
cure of my disease?
Doctor, is there any new drug
for my asthma?
Currently the only possible cure
available is Immunotherapy.
The physicians/
Pulmonologists
frequently
encounter few
questions

12. Introduction
 Asthma is a major global health problem. In Bangladesh, an
estimated 7 million people, including 4 million children, suffer
from asthma related symptoms.
 Allergic rhinitis is also a global health problem affecting at
least 10-50% of the population.
 Upto 78-93% of patients with asthma have concomitant AR
and 38% of AR have asthma. [Spector 1997, Kapsali 1998,
Waibal KH 2005]
 Among chronic illnesses, allergic rhinitis and asthma are the
leading causes of absenteeism,
 With 2 million annual lost school days attributed to allergic
rhinitis.

13. Introduction…
 A lot of money is spent every year for pharmacotherapy which
aims to reduce symptoms rather than targeting immunologic
disease process,
 Where immunotherapy (IT) is the only treatment option that
offers long term modifications of the underlying immune
system and is the only potential cure for the atopic patients.
 It can modify the immune response to allergens and alter the
course of diseases
 It should be based on allergen sensitization, not on the disease

14. Introduction…
Most patients with asthma have an
allergic component to their disease.
 Allergic food and animal can easily
be avoided but some allergens
like mite can't be, as it is
ubiquitous.
So it is wise to immunize
against mite allergen in mite
allergen positive patient along with
avoidance of allergic foods and
contact with animals to prevent
bronchial asthma and allergic rhinitis.

19. Multitest IIMultitest II

20.  Allergic Rhinitis is a common respiratory illness that causes
significant morbidity and affects the quality of life,
productivity and other co morbid conditions like asthma
 Inflammation to the mucosal lining of the nose caused by
inappropriate hypersensitivity reaction to an aeroallergen
 Symptoms include rhinorrhea, nasal congestion, obstruction,
pruritis

21.  Affects approximately 1/3 of US citizens
 Lost work/school days
 Costs of continued medication
 IgE mediated immune response, with mast cell activation and
release of cytokines
 Occurs after exposure to indoor/ outdoor allergens

22. Asthma and rhinitis as different Aspects of a sinlge disorder
[The nose-lung interaction in allergic rhinitis and asthma:[The nose-lung interaction in allergic rhinitis and asthma: united
airways disease - Passalacqua,G.Ciprandi & G.W.Canonica
2004]
Allergic Rhinitis and Asthma frequently occur together
40% of allergic rhinitis patients have asthma
80% of asthma patients have concomitant Rhinitis symptoms
[European Respiratory Disease 2006 ]

23. Bronchial biopsioes after
Specific provocation in
patients with rhinitis or
asthma
(Crimi E et al, JAP 2001)
ASTHMA
RHINITIS ALONE
Same inflammation

24. Airways response to allergenAirways response to allergen
in rhinitis and asthmain rhinitis and asthma
WHAT MAKES THE DIFFERENCE?WHAT MAKES THE DIFFERENCE?
The Allergen Dose!

25. Asthma and Rhinitis
Allergy control impacts asthma
as well as allergic rhinitis
(AR).
Allergic rhinitis as a predictor
for wheezing onset in school-
aged children.
[Rochat et al, JACI 2010]
Perennial rhinitis: independent
factor for developing asthma
[Leynaert et al, J Allergy Clin
Immunol 1999]

26. Allergic
Rhinitis
Upper Respiratory
Infection
Nasal
Polyposis
SinusitisAsthma
Otitis Media
With Effusion
Interrelationships between Allergic Rhinitis
and Associated Airway Diseases

27. naso-bronchial reflex
INFLAMMATION
allergen
cytokines bone marrow
nose
bronchi
bronchial
hyperreactivity
physical filter function
adhesion molecules
viral infection

28. Nasal allergen challenge
Increases bronchial reactivity
Induces bronchial inflammation
(Littell 1990, Corren 1992, Small
1989)

29. Bronchial endoscopic challenge
With allergen
Induces nasal inflammation

30. Allergic rhinitis is a risk factor for asthma
(Co-Existence of Asthma and Allergic Rhinitis: A 23-
Year follow Up Study of College Students)
23-year follow-up of college freshmen undergoing allergy testing; data based on 738
individuals (69% male) with average age of 40 years.Adapted from Settipane RJ et al Allergy
Proc 1994;15:21-25.

31. Untreated rhinitis increases the risk of asthma attacks
ousquet, Clin Exp Allergy 2005
asthma
Asthma + rhinitis

32. Diagnostic tools / The problem
Differently from asthma / there is no reliable or
Standardized objective measurement
No objective evaluation of severity
No tool is capable to discriminate allergic and nonallergic rhinitis
No tool is capable to discriminate healthy and rhinitics

33. ARIAARIA is the firstis the first
Evidence Based DocumentEvidence Based Document
endorsed byendorsed by WHOWHO
(J.A.C.I.(J.A.C.I. NovemberNovember 2001)2001)

35. When symptoms persist
despite optimal medical
management,
Immunotherap
y is an option
both for Allergic
Rhinitis and
Asthma

36. allergen
avoidance
indicated
when possible
allergen
avoidance
indicated
when possible
pharmacotherapy
safety
effectiveness
easy to be administered
pharmacotherapy
safety
effectiveness
easy to be administered
immunotherapy
effectiveness
specialist prescription
may alter the natural
course of the disease
immunotherapy
effectiveness
specialist prescription
may alter the natural
course of the disease
patient's
education
alwayAs indicated
patient's
education
alwayAs indicated
patient
Modified from

37. mild
intermittent
Mild
persistent
Moderate-
severe
intermittent
Moderate-
severe
persistent
Allergen avoidance
Decongestant (<10 days)
Nasal steroid
2nd Generation antihistamine
Immunotherapy
TREATMENT OF ALLERGIC RHINITIS
ARIA -Allergic Rhinitis and its Impact on Asthma
Cromones
Antileukotrienes (if asthma)

38. IMMUNOTHERAPY IN ASTHMA (2005)
Immunotherapy
Pharmacotherapy
GINA I
Asthma
(Intermittent)
GINA II
Asthma
(Mild
Persistent)
GINA III
Asthma
(Moderate
Persistent)
GINA IV
Asthma
(Severe
Persistent)

39. Immunotherapy
Allergen immunotherapy is the administration of
gradually increasing quantities of an allergen
vaccine to an allergic subject reaching a dose
which is effective in ameliorating the symptoms
associated with subsequent exposure to the
causative allergen
(WHO Position Paper 1998)

40. Immunotherapy…
Immunotherapy or allergen vaccination involves
titrated exposure of allergen to patients to induce
immunologic tolerance
It is the practice of administering to allergic subjects
increasing amount of allergens/ allergen extract to
achieve hypo sensitization, i.e., to reduce the symptoms
occurring during the natural exposure to the allergen
itself
Immunotherapy is the only treatment option that offers
long term modifications of the underlying immune
system and is the only potential cure for the atopic
patients
Should be considered for patients with moderate to
severe allergic rhinitis that is not responsive to usual
treatments

41. Immunotherapy…
Consists of small amount of allergen extract given
sublingually or Subcutaneously over the course of few
years
Disease accepted to be treated by immunotherapy-
Allergic rhinitis, allergic asthma, allergic
conjunctivitis, insect sting hypersensitivity
Disease not accepted to be treated by
immunotherapy- Food allergy, urticaria, atopic
dermatitis

42. Immunotherapy…
In order to give immunotherapy, specific allergens
must be known
Vaccine should use standardized extracts
Exact mechanism is not clear
Immunotherapy requires a compliant patient,
due to its long duration

43. Original article by
Leonard Noon in
10.6.1911
Noon and Freeman
Brief history of Immunotherapy

44. Brief history of Immunotherapy..
1565 –Leonardo Botello described Seasonal Allergy
1819 –Bostock described the Classical Case of Hay Fever
1872 –Morrill Wyman described Autumnal Catarrh
1873 –Blackley - Grass Pollen Counts
19001900– Curtis immunized people with aqueous extract of whole
weeds
1903– Dunbar immunized subjects who had grass-sensitive hay fever
with animal derived (horse and goose) grass pollen antisera to
subject’s nasal mucosa
1907–Besredka and Steinhardt encountered anaphylactic reaction
during immunotherapy due to immunizing too rapidly or with too
large dose of allergen
19101910–Leonard Noon and Cantab introduced Subcutaneous injections
of pollen extracts. He also introduced weight units for pollen doses
and quantization of individual sensitivity by in vivo testing.
1913–Clowes Demonstrated a 1000 fold increase in resistance by
conjunctival testing

45. Brief history of Immunotherapy..
1914 -Robert Cooke developed Basics of Immunotherapy as
practiced today, PNU –Kjeldahl method, Mechanisms of
Immunotherapy, Blocking antibodies and Dosage and testing
techniques. Freeman and Koessler observed that immunotherapy
produced long lasting results
1915 - Cooke(1915): formally introduced immunotherapy into the
USA by reporting the treatment by pollen immunization of 114
patients with hay fever and asthma.
1968 –Norman - Immunotherapy replace Desensitization
1980’s1980’s –Newer routes of drug delivery introduced - Sublingual
Immunotherapy
1990’s –Other routes developed: Oral microencapsulated, Local
Nasal, Bronchial
19981998 –60 million patients annually treated in the world, including 33
million injections every year in USA aloneA panel of experts of
the WHO concluded that SLIT is a viable alternative to SCIT.
20022002 - 50% of Immunotherapy in Europe is Sublingual

46. Brief history of Immunotherapy..
The history of SLIT is short and encompasses a period of only
around 25 years
Low-dose sublingual immunotherapy (SLIT) for respiratory allergy
was firstly described in a controlled trial in 1986
The original rationale of SLIT was that of achieving a prompt and
rapid absorption of the vaccine through the oral mucosa. It then
became the most used non-injection route for immunotherapy in
Europe
After a review of the literature existing in 1998, a panel of experts
of the WHO concluded that SLIT is a viable alternative to SCIT

47. Brief history of Immunotherapy
The sublingual approach was initially proposed empirically,
without knowledge of the bio-distribution of allergens and of the
possible mechanism of action
As a consequence, the practical aspects of SLIT (i.e., allergen dose,
frequency of administration, build-up modality) were selected by
investigators on the basis of personal experience. The result is
significant variability in administration schedules, dosages, and
duration
Because of regulatory issues SLIT is not used worldwide but is
employed in clinical practice in Europe and other regions including
South Africa and Latin America

48. Allergen specific immunotherapy vs
pharmacologic treatment
Specific immunotherapy does not take the position of
being an ultimate treatment principle
It should be part of the global treatment and should be
used in the early phase of disease
Modified from ARIA JACI 2001

49. Mechanisms

50. Mechanisms..
How Immunotherapy (IT) works?
Allergen immunotherapy is the only treatment that can modify
the natural history of allergic disease
It is a method of allergy treatment that uses an allergen solution
that reduces sensitivity to allergens
Allergic symptoms improve as the allergic sensitivity improves
IT can prevent the onset of new sensitizations
Administered for several years (3 to 5 years) - efficacy is
maintained for up to 3 or more years after discontinuation

51. Mechanisms..
It has been demonstrated that IT decreases allergen-induced
inflammation in allergic rhinitis and allergic asthma.
Airway inflammation in asthma may represent a loss of normal
balance between two “opposing” populations of Th lymphocytes:
Th1 and Th2.
Th1 cells produce IL-2 and IFN-γ, which are critical in cellular
defense mechanisms in response to infection.
Th2, in contrast, generates a family of cytokines (IL-4, 5, 6, 9,
and 13) that can mediate allergic inflammation.
Immunotherapy (IT) expands allergen specific TH1 immunity &
suppresses the TH2 response resulting in clinical anergy.

52. Mechanisms..
It has long been known that oral administration of an allergen
favours the development of tolerance.
Current understanding is that regulatory T cells secreting TGF-β
are involved in this type of tolerance.
Administration of high-dose allergen immunotherapy by means of
SC injection also induces the development of regulatory T cells,
with evidence that the secretion of both IL-10 and TGF-β is
important in the mechanism of tolerance

53. Th2
TCD4+ IT
IMMUNE DEVIATION?
ANERGY?
BOTH?
Mechanisms..
Th1

54. Mechanisms..
Successful immunotherapy is associated with:
Shift from TH2 to TH1 lymphocyte immune response to
allergen
Immunologic tolerance – decline in allergen specific
responsiveness
Increases in allergen specific IgG blocking antibody

55. Mechanisms..
Mechanism of action of Immunotherapy: [Summary of
Stephen Durham 1998]
Reduces both early and late phase reaction
Reduces concentration of inflammatory mediators
Reduces nasal mast cells, eosinophils & eosinophil
cationic protein
Modify T Lymphocyte response
Increases gamma interferon, IL-2,12
Not known whether immune deviation due to anergy of
Th2/ Th0 or increase of Th1
Amplification of CD8 cells – downregulatory

56. Mechanisms..

58. Types of Immunotherapy
Subcutanous Injections [SCIT]:
(over 90 years-mainstay of therapy in the USA)
New Methods
Sublingual Immunotherapy [SLIT]
(over 25 years in Europe) [Nelson(1993) Chando(1995)]
Intranasal/ Local nasal (LNIT):
Aqueous (Andri,1995),Powder (Andri,1996)
Oral Immunotherapy (OIT) (Bordignon,1994)
Oral encapsulated [Litwin (1997), Van Densen(1997)]
Local bronchial (LBIT) [Bjorksten (1994)]

59. Types of Immunotherapy…
Subcutanous Injections [SCIT]:
(over 90 years-mainstay of therapy in the USA)
Conventional
Months to maintenance
Short term
Seven preseasonal injections
Rush
 Days/ weeks for maintenance
 Rapid relief & good compliance
 Hospital admission
 High systemic reactions

60. Types of Immunotherapy…
Sublingual Immunotherapy [SLIT]:
allergen kept under the tongue for 1-2 minutes, then
swallowed (the sublingual- spit mode is no longer in
use).
Intranasal/ Local nasal (LNIT):
allergen sprayed into the nostrils as aqueous solution or
dry powder.
May be indicated in carefully selected adult patients (may
be in children) with rhinitis caused by pollen and possibly
by mites.
Oral Immunotherapy (OIT)
allergen immediately swallowed, as drops, tablets or
capsules.
Oral encapsulated
Local bronchial: allergen inhaled with a deep inspiration.

61. Subcutanous Injections (SCIT):
SIT is able to alter the natural course of allergic diseases
1- Reduction of inflammation
2- Reduction of non-specific bronchial
hyperresponsiveness
3- Prevention of new IgE sensitivities
4- Prevention of asthma in patients with allergic rhinitis
5- Duration of efficacy after cessation

62. Subcutanous Injections (SCIT)…
SCIT is the only approved route of administration in USA
It normally involves a weekly SC injection of an extract of
the allergen, in solution, in increasing doses until a standard
maintenance dose is reached.
This dose is then injected SC on a regular basis (at intervals
of approximately 20 days) for not less than 3 years for
perennial allergens.
Start at early age, so that adverse changes to the immune
system can be prevented before they become irreversible

63. Subcutanous Injections (SCIT)…
Low dose to start
Increased weekly
Maximum dose at 12 weeks
Maintenance every 3-6 weeks for 3-5 years
Immediate and late reactions

64. Subcutanous Injections (SCIT)…
Injection techniqueInjection technique
 Use upper outer surface of arm
 Ensure sterile technique
 Use 1 ml tuberculin syringe with 3/8 inch 26 or 27 gauge
needle
 Inject at 45º by deep subcutaneous route
 Record any local/ systemic reaction

65. Non-injection or local routes
Bronchial and oral route:
not recommended for clinical use, due to insufficient
demonstration of efficacy and the occurrence of side
effects.
Nasal IT (LNIT) and Sublingual IT (SLIT):
can be considered as viable alternatives to subcutaneous
administration.Based on the available literature.
WHO Position Paper 1998

66. Sublingual Immunotherapy (SLIT):
Indication of SLIT
As per guidelines, SLIT is indicated in
patients with allergen-positive mild to moderate asthma or
allergic rhinitis or both
those who refuse injections or
previously experienced severe adverse reactions to SCIT.
Absorption, mechanism and duration
Sublingual immunotherapy uses the principle of oral absorption
Easily reaches submandibular lymph channels
Faster than subcutaneous route (absorption)
Higher the dose, earlier the effect
Duration is 2 to 3 years on an average, can be continued upto 5
years
In Nearly 70 to 80 % the treatment can be stopped much earlier

67. Sublingual Immunotherapy (SLIT)..
First described in a controlled trial for respiratory allergy in 1986.
After nearly 10 years of starting, the procedure picked up in USA
and UK in few centres
WHO approved this modality
The extract is kept under the tongue for a couple of minutes and
then swallow it or Spit it.
Dose of allergen is greater than subcutaneous immunotherapy
(about 3-300 times higher)
May be indicated in pollen and mite induced rhinitis and asthma
in adults and children, using maintenance dosages 5 -100 times
higher than injection IT.
RCTs have demonstrated the efficacy of sublingual
immunotherapy

68. Sublingual Immunotherapy (SLIT)..
SLIT can be administered either
Pre seasonally (start prior to the season and stop at the
beginning at the season) – commonly used for pollen allergy
OR
Pre-co seasonally (start prior to the season and stop at the end
of the season) – commonly used for pollen allergy OR
Continuously – commonly used for house dust mite
The most used regimen includes once daily or alternate day or once/
twice weekly administrations.
The vaccine or solution is usually administered in the morning with
the patient in fasting state, but may be administered at any time of
the day.

69. Sublingual Immunotherapy (SLIT)..
SLIT can be delivered by means of two methods:
Sublingual spit method where the vaccine is kept
under the tongue, for a short period and then spat out
and
Sublingual swallow method where the vaccine is
kept under the tongue for 1-2 minutes and swallowed.
The sublingual swallow method is used in majority of the
studies and regarded as more appropriate and
advantageous way to administer the allergen
(because the sublingual spit method led to a partial loss
of allergen).

70. Sublingual Immunotherapy (SLIT)..
SLIT is self-administered
Usually self managed by the patient at home
Thus detailed instructions, schedule of administration,
and possible side-effect discussions are mandatory and
also
Requires concerns about compliance and monitoring

71. Sublingual Immunotherapy (SLIT)..
SLIT is currently marketed by several European and Indian
manufacturers, standardized either biologically or
immunologically.
The allergen extracts, administration schedules and amount of
allergen(s) largely vary, depending on the manufacturer.
The vaccine of SLIT is available in two principle pharmaceutical
forms.
Buffered solution to be delivered by drop-counters, droppers,
pre-dosed actuators or disposable single dose vials.
Tablets with appropriate composition facilitating slow (1-2
minutes) dissolution in the mouth upon contract with saliva.

72. Sublingual Immunotherapy (SLIT)..
Advantages
> 50% Allergologist switched over to SLIT
Rarely produces any reactions
More compliant to therapy
Children can also take
Disadvantages
Side effects are extremely rare
Mouth itching and soreness of throat
Sneezing
Increase in asthma symptoms initially ( yet to report,
only theoritical )

73. Sublingual Immunotherapy (SLIT)..
Ideally, SLIT should be used in an integrated treatment
plan, including avoidance measures and appropriate
pharmaceutical therapy.
SLIT traditionally involves a ‘Build-up phase’ (with
gradually increasing doses) of 4-6 weeks, followed by a
‘Maintenance phase’ with maximum dose. This
approach is similar to SCIT but more accelerated.
The vaccine is prepared in separate vials at increasing
concentrations.
The treated subject starts the lowest concentration and
gradually increases using the different doses
preparations, until the maintenance dose is reached.

74. Clinical efficacy of SLIT
In Bangladesh, a double blind placebo-controlled RCT
was conducted at NIDCH
(Rezaul Huq et al 2009)
on efficacy of SLIT on 64 patients with house-dust mite
positive moderate persistent bronchial asthma with
allergic rhinitis
 and patients were followed up by asthma specific
quality of life questionnaire
for one year

75. Clinical efficacy of SLIT
In this study, efficacy and safety of SLIT was assessed
as compared with those of placebo therapy
In patients of moderate bronchial asthma with allergic
rhinitis
Inclusion criteria was - Mite allergen positive patients ie.
skin prick test positive (wheal>5mm2 )
 To standardized extract of Dermatophagoides
pterosynsinus (D.pt) and Dermatophagoides farinae
(D.f)
This study showed improvement in symptoms of
bronchial asthma with allergic rhinitis
The Number Needed to Treat (NNT) was 3.4

76. SCIT vs. SLIT
SCIT
 requires frequent injections
 which often results in patient non-compliance
and also has got safety concern,
 so not liked by many physicians.
SLIT
 on the other hand, is a non-injection IT method
 It is very promising
 as it has a very good safety profile
and is usually self administered at home
(better patient compliance)

77. SCIT vs. SLIT..
SLIT has now been used in Europe for
over 25 years
 but not yet approved in USA studies are
on-going
SLIT is effective but not as effective as
SCIT
SLIT requires daily administration at
higher concentrations than used for SCIT
safer than SCIT
SLIT does have long-term benefits but not
as well documented as for SCIT

79. Supportive Information on
Efficacy of Immunotherapy
Immunotherapy Committee
American Academy of Allergy, Asthma and
Immunology (AAAAI)

80. Indications of Immunotherapy
IgE mediated respiratory allergy
Skin test or RAST positive for a specific antigen
No relief of symptoms with environmental changes
or not possible to avoid exposure
Failure to obtain relief with medications or tolerate
medications
Unwillingness to take long term medications
Significant allergic upper airway or ocular disease

81. Indications of Immunotherapy..
IN PREGNANT PATIENTS
Immunotherapy should not be initiated during
pregnancy
Immunotherapy can be continued in pregnancy
if she has been tolerating it well
No teratogenesis observed

82. Patient selection for Immunotherapy
 Significant symptoms induced by one or few allergens
 Proven allergy with skin test or RAST
 Attempts to avoid allergens fail or impractical
 Treatment with medicine is not fully successful or when
medication is not well tolerated.
 Young patients without chronic irreversible changes in
the upper airways
 Patient needs to be motivated and compliant with
treatment
 No contra-indications (severe asthma, Beta blockers,
inability to comply with IT)

83. Factors to be considered before prescribing
immunotherapy
Presence of an IgE-mediated disease (allergic rhinitis,
allergic asthma)
Symptoms are caused by specific allergen(s)
Severity and duration of symptoms
Response to allergen avoidance and pharmacotherapy
Contraindications
Cost-benefit ratio
Patient compliance
Availability of standardized extracts
Modified from WHO, 1998

84. GUIDELINES FOR IMMUNOTHERAPY – mainly for SCIT
American Academy of Allergy, Asthma and Immunology
(AAAAI)
Should not be self administered
Physician’s office, emergency equipment available
Informed consent
High potency extracts needed
Appropriate dose reductions made in delays, vial change,
reactions
Universal Precautions
Individual dosage schedule
Store extracts at 4 degree centigrade
Clinical & Peak flow before & after Injection
Stays at clinic for at least 30 minutes
Local swelling > 50mm requires dosage reduction
No relief for 2 years- discontinue
High dose therapy usually for 5 years

85. Contraindications for allergen immunotherapy
Absolute
Concomitant use of Beta Blockers
Risk of Anaphylaxis
Previous Anaphylactic reaction to Immunotherapy
Lack of adequate resuscitation facilities
Serious immunopathologic diseases and immunodeficiencies.

86. Contraindications for allergen immunotherapy...
Relative
If FEV1/PEFR < 70% predicted
Unstable Asthma [uncontrolled by pharmacotherapy] (FEV1<70% )
Nocturnal Asthma, Use of bronchodilator more than thrice a
week, Diurnal variation >20%, Bronchodilator reversibility >20%
Other significant medical diseases
Autoimmune disease or Malignancy
Unstable coronary artery disease
Pregnancy – do not initiate
Bronchospasm to previous injection
Children <5 years of age
Beta Blocker when administered topically (eg- eye drops)
Poor compliance

87. WHO position paper on
immunotherapy
5- Safety of SIT:
 The major risk for SIT is anaphylaxis
 Asthma is a significant risk factor for systemic
reactions. Uncontrolled asthma or FEV1<70%
predicted are risk factors for developing a bronchial
reaction during SIT
 SIT should be administered by or under the close
supervision of a trained physician able to recognize
early symptoms of anaphylaxis and to administer
emergency treatment.

88. WHO position paper on immunotherapy…
Safety of SIT:Safety of SIT:
 Millions of subcutaneous immunotherapy injections are
administered annually.
 The risk of a fatal or near-fatal systemic reaction is extremely
small but not completely absent.
 Adverse events can be further reduced if certain precautions
are taken.
 Physicians prescribing or administering subcutaneous
immunotherapy should be aware of these risks.
 And institute appropriate procedures to minimize them.

89. WHO position paper on immunotherapy…
Safety of SIT:Safety of SIT:
 IT should be administered by or under the close supervision of
a trained physician able to recognize early symptoms of
anaphylaxis and to administer emergency treatment
 SLIT is self-administered at home
 Patients should be informed of the potential risks of a systemic
reaction and how to treat such a reaction should it occur
[Alvarez-Cuesta et al, Allergy 2006]

90. WHO position paper on immunotherapy…
Safety of SIT:Safety of SIT:
 In post-marketing studies, the overall rate of side effects (all
grades) ranges between 3% and 8% of patients
 The side effects are usually mild and treatment discontinuation
is rarely required
 The most frequent reported side effects are
 (Gastrointestinal side effects : dose-dependent)
- oral itching/ swelling
- nausea, stomachache
- headache, arthralgia
 Severe reactions are rare

91. WHO position paper on immunotherapy…
Safety of SIT:Safety of SIT:
 Fatality: [Lockey RF et al JACI 1987, Reid MJ
et al, JACI 1993]
Period 1945-1984: 46 Fatalities
Period 1985-1989: 17 Fatalities
Estimated risk for fatal reactions less than 1
per 2 million injections
 No life-threatening side effect or fatality has
ever been reported since the introduction of
SLIT in 1986

92. Effects of immunotherapy
Symptom improvement and/or reduction of the need for
symptomatic drugs in allergic rhinitis and asthma.
Studies demonstrated both long term and short term benefits
Initial IT significantly reduced symptoms. [Donovan ,1997]
Trial of discontinuation attempted after 5 years
On stopping IT partial return of mediators, decline in IgG
noted, but Seasonal increase in IgE did not occur.
[Donovan ,1997]
Beneficial effects persists for years after full course of IT.
[Medin,1995]
Prevention of the onset of new skin sensitizations.
[Marogna,2004]
Prevention of the onset of asthma.

93. RISK FACTORS
IN NONFATAL REACTIONS
Uncontrolled asthma
FEV1 < 70%
Beta blockers
High dose therapy
Rush immunotherapy
Incorrect technique
Errors in dosage
IN FATAL REACTIONS
Symptomatic asthma
High degree of allergen
sensitivity
Injections during seasonal
exacerbation
Injections from new vials
Errors in dosage
Beta blockers

94. PRECAUTIONS
Administer cautiously in all asthmatics
PFT/ Peak flow >70%
PFT/ Peak flow before patient leaves clinic
Stick to dosage schedule
Irregular patients at risk of reactions
If schedule needs to change – Allergist
All vials to be properly labelled
Check patients name and number and vial and dosage at each
visit
Even after reaching maintenance – decrease dose when new
vial is started
Fever, acute asthma skip the injection

95. EFFECTS OF WITHDRAWAL
Medin G (1995)
Beneficial effects persists for years after full course of IT
Studies demonstrated both long term and short term benefits
Trial of discontinuation attempted after 5 years
Donovan (1997)
Initial IT significantly reduced symptoms
On stopping IT partial return of mediators, decline in IgG
noted
Seasonal increase in IgE did not occur
Symptom improvement persisted

96. Why immunotherapy
fails ?
wrong set up
wrong patient
wrong allergen(s)
wrong dose
wrong duration
Why immunotherapy
succeeds ?
right set up
right patient
right allergen(s)
right dose
right duration

97. Is it useful?
 Large Volume of data in favour
 Van Metre ( 1980)
Decrease in symptoms
Decrease in medication use
Improvement limited to antigens used
 Horak (1993)
Immunotherapy is an integral component in treatment strategy
Standardized extracts improve treatment safety and efficacy
 British Society Position Paper – 1993
Immunotherapy reduces inflammation and bronchial hyper responsiveness
 European Academy of Allergy & Immunology – 1993
Immunotherapy influences favourably the progression of clinical disease
 Canadian Guidelines (1995)
Immunotherapy is effective in patients with allergy to insect stings, allergic
rhino conjunctivitis and in some patients with asthma who have been correctly
diagnosed through a cautious history and corroborated with positive skin test
results

98. Is it useful?..
 Donovan (1996)
Nasal symptoms significantly less
 Schoen wetter (1996)
Correct allergen, adequate dose, appropriate patient, safe and effective
 Creticos ( 1996)
Decreases hay fever symptoms, skin sensitivity & sensitivity to bronchial
challenge
 New Zealand, Australia and Australasian Society on Allergy – 1997
Immunotherapy should not be regarded as an alternative to established forms
of preventive therapy
Safe and Effective
 Adkinson (1997)
Children with moderate to severe perennial asthma
Not much benefit
Small number of patients
Too many aeroallergens
 Timothy Craig(1998)
Data to support use is less concrete

99. Is it useful?..ABRAMSON – 1995 – Adults
ROSS – 2000 - Adults
20 Randomized Placebo Controlled Double Blind trials between 1966-80
Concluded that Immunotherapy is effective
TO OVERTURN THESE RESULTS 33 NEGATIVE STUDIES ARE REQUIRED
ABRAMSON – 1995 – Adults
ROSS – 2000 - Adults
Reductions in symptoms
Decreased need for asthma medications
Improved lung functions
Decreased bronchial hyper reactivity
Arnaldo (1998) Children
27/29 studies of controlled pediatric studies with 1443 children aged 2-14
Beneficial effects on natural history
Some had total remissions
Needed to complete immunotherapy
Concluded only curative treatment for asthma, safe
Prevention of asthma
Preventing disease progression
Preventive immunotherapy – Jacobsen 2001
Prevention of Asthma Treatment – PAT study - 2002
META ANALYSIS

100. Is it harmful?Side Effects Usually minor
Timothy Craig 1998
 Local Swelling, redness in 15%
British Society of Adverse events 1993
 1/500 injections
Hejjaoui 1992, Wells 1996 Risk increases with
 Rush Desensitization
 Use of high doses
 Uncontrolled asthma
 Strongly positive skin tests
 Change of vials
 Prior Anaphylaxis
Systemic Reactions
Portnoy 1994 – Rush Therapy – 27%
Nielsen 1996 - Rush Therapy – 33%
Greinder 1996 - Rush Therapy – 36%
Greinder 1996 - Conventional <1%

101. Is it harmful?Committee on safety of medicines – BMJ 1986
1/ 27,854 injections
In 29 years, 14,59,273 courses of treatment – 29 deaths
Lockey and Reid 1993
24 deaths from 1959-1984
17 deaths from 1985 –1989
ERRORS OF TREATMENT

102. Clinical efficacy of SLIT
The first meta-analysis of SLIT for allergic rhinitis
included 22 DBPC trials and 979 patients up to
September 2002 (Canonica).
It concluded that SLIT was significantly more
effective than placebo in rhinitis caused by pollens
and mites.

103. Clinical efficacy of SLIT..
Limitation of the study were significant heterogeneity
among the included studies
and inability to differentiate the effects of various dosages
The optimum dose and duration of therapy remained
unanswered
The review concluded that SLIT is effective for allergic
rhinitis and has been proven to be safe route of
administration

104. SLIT with mites
Bousquet et al, Allergy 1999
60
70
80
90
100
110
FEV1(%pred)
baseline 1 yr 2 yr
IT
placebo
350
375
400
425
450
morningPEFR(ml)
baseline 1 yr 2 yr
IT
placebo
FEV1 PEFR
p<0.01
p<0.01
p<0.01

105. Sublingual HDM immunotherapy
Passalacqua et al, Lancet 1998Passalacqua et al, Lancet 1998
25201510500
0
25
50
75
100
125
150 placebo
SIT
duration of study (months)
symptomscores

106. Long-lasting efficacy of SLIT: children with asthma
DiRienzo et al Clin.Exp.Allergy. 2003
The long-lasting effect has been demonstrated in children with mite-induced
asthma in a 10 year prospective study.

107. Specific immunotherapy prevents the development
of asthma in children with allergic rhinitis
(the PAT study)
Moller C et al, JACI 2002
205 children with rhinitis
age: 6-14 yrs
grass or birch allergy
3 yrs immunotherapy
SLIT CONTROL
%
60
19
40
32
No asthma
Asthma
Moller C et al, JACI 2002

108. Specific immunotherapy
has long-term
preventive effect of
seasonal and perennial
asthma: 10-year follow-
up on the PAT study
Jacobssen, Allergy 2007

109. SLIT NO SLIT
37
8
26
18
NO ASTHMA
ASTHMA
PRESENCE OF ASTHMA AFTER 3 YEARS
Co-seasonal SLIT reduces the development of asthma in
children with allergic rhinitis.
Novembre E. et al, JACI 2004
Randomized, open,
controlled
79 children
Allergic rhinitis only
Follow-up: 3 yrs

110. Allergen immunotherapy (IT) for asthma
Abramson, Weiner and Puy,
Cochrane Database Systematic Review 2003
76 trials with 3,188 patients
Significant improvement in asthma
symptom scores
Significant reduction of allergen specific
bronchial hyperreactivity
Some reduction also in non-specific
bronchial hyperreactivity
It would have been necessary to treat 4 (95% CI 3 to 5) patients with
IT to avoid one deterioration in asthma symptoms, and overall to treat
5 (95% CI 4 to 6) patients with IT to avoid one requiring increased
medication.

111. Efficacy of SLIT
Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis
Wilson DR et al. 2005
 Systemic review of literature in Cochrane
library
 22 clinical studies, a total of 979 patients
double-blinded, placebo-controlled, parallel-
group studies
 highly significant reduction in symptoms as
well as definite decrease in medicine intake
for symptoms

112. Efficacy of SLIT..
a meta-analysis in asthma was reported, including 25 trials
Calamita 2006
a meta-analysis in asthma was reported,
including 25 trials(either open or blinded) and
involving more than 1,000 adults and children.
This meta-analysis demonstrated a significant
effect of SLIT for most of the considered
outcomes (symptoms medications, pulmonary
function, overall improvement), with the
exception of asthma symptoms alone.

113. Efficacy of SLIT..
in Allergic rhinitis
in paediatric patients (4 to 18 years)
Annals of Allergy Asthma and Immunology
Penagos M. et al. 2006
This Meta-analysis of SLIT for allergic rhinitis in pediatric
patients (aged 4–18 years) involved 10 trials and 484
subjects.
This Meta-analysis showed
SLIT was significantly more effective than placebo,
as assessed by the reduction in both symptom scores
and rescue medications usage in paediatric patients
with allergic rhinitis.

114. Efficacy of SLIT
in Allergic rhinitis
in paediatric patients (4 to 18 years)
Another meta-analysis was performed for
asthma in pediatric patients (Penagos et al.,
2008).
This review included 9 DBPC trials and 441
patients, and found a significant effect of SLIT
on both asthma symptoms and rescue
medication usage.

115. Allergen immunotherapy for asthma
Abramson MJ, Puy RM, Weiner JM, Allergy 1999
Authors' conclusions:
 Immunotherapy may reduce asthma symptoms and use
of asthma medications
 but the size of the benefit compared to other therapies
is not known
 The possibility of adverse effects (such as anaphylaxis)
must be considered

116. Novel approaches
New immunological treatment modalities for allergic
diseases are presently under investigation:
Anti-IgE antibodies combined with IT
Liposome vaccines
Adjuvants
Peptide vaccination
Recombinant allergens
cDNA vaccines

117. Remember
Take your time and review the records to ensure that:
you are giving the right dose of the right allergy
immunotherapy vial to the right patient, because
No patient ever died (from an immunotherapy
injection) waiting to receive an injection
The extra time and wait will not harm you or the patient
but
Dosing errors and allergy injections to actively
symptomatic patients can do serious harm

119. Conclusion
Asthma and Allegic rhinitis are interrelated.
For both the conditions, Immunotherapy (IT) is
a viable option
IT is an effective and potentially disease
modifying treatment in asthma, allergic rhinitis
and stinging insect anaphylaxis
IT works by altering the immunologic response
and reduces bronchial hyperresponsiveness
Effectiveness of IT depends on appropriate
dose and duration of treatment
Based on the literature, SIT should be used in
association with standard medications

120. Conclusion..
Asthma and Allegic rhinitis are interrelated. For both the
conditions, Immunotherapy (IT) is a viable option
IT is an effective and potentially disease modifying
treatment in asthma, allergic rhinitis and stinging insect
anaphylaxis
IT works by altering the immunologic response and
reduces bronchial hyperresponsiveness
Effectiveness of IT depends on appropriate dose and
duration of treatment
Based on the literature, SIT should be used in association
with standard medications

121. Conclusion..
Immunotherapy may reduce asthma symptoms and
use of asthma medications.
Appropriate safety measures to be taken to prevent or
reduce adverse reactions.
SLIT is potentially a significant advancement in
immunotherapy.
Many questions still remain unanswered, including
effective dose schedule, timing, mechanism and
safety in high risk groups.
We are looking forwards for the results of the
ongoing studies.

122. Conclusion
No doubt Immunotherapy, both SCIT and SLIT, are
costly, especially for the people of Bangladesh
But life is more important than money
Many patients are eager to spent all of his/her
belonging for the cure of Asthma
Improvement of quality of life will be associated with
relief of Asthma or related diseases when there is a
cure

123. Conclusion..
We, the people of this world, hoping for the total cure
of asthma
So far Immunotherapy is the only available cure
known
Why should not we try to conquer asthma and related
airway diseases with the help of Immunotherapy?
That day is no longer far away when a children with
asthma will not be afraid of playing

124. Take Home
Messages
• AR and Asthma
comorbidity is a clinical
reality
• Inflammation is The basic
background
• The ARIA classification is
working in real life
• Rhinosinusal infections
are frequent
 in asthmatic children
Recommendations
1- Patients with persistent
rhinitis should be evaluated
for asthma
2- Patients with persistent
asthma should be evaluated for
rhinitis
3- A strategy should combine
the treatment of upper and
lower
airways in terms of efficacy
and safety