Allergen immunotherapy (AIT) involves controlled exposure to allergens to reduce symptoms of allergic diseases like rhinitis, asthma, and conjunctivitis. It was first attempted in the early 1900s by immunizing people with plant extracts. While initial attempts caused adverse reactions, later studies found controlling the dose prevented this. Today, AIT is accepted for treating respiratory allergies and insect sting reactions but not food allergies or other conditions.
Dr. A Sumathi - LINEARITY CONCEPT OF SIGNIFICANCE.pdf
Presentation allergic rhinitis madan
1. Dr Madan
Jr ENT
ALLERGIC RHINITIS & VMR
AETIOLOGY, PATHOGENESIS,
CLINICAL FEATURE
TREATMENT AND ROLE OF
IMMUNOTHERAPY
2. • ―IgE mediated hypersensitivity disease of mucous
membranes of nasal airways characterized by
sneezing, watery nasal discharge , itching and nasal
obstruction‖
Durham et al.,1999
• Clinically defined : two or more nasal symptom:
running
blocking
itching
and sneezing
Definition
3. • Important health problem : social life, school performance,and work
productivity.
• Global health problem
• Prevalence : 10-20%
• Higher in pediatric age group - 42% - Wright et al .,1994
• AR -> 50% of all allergy cases seen in India
• Affecting every 6th person
• Peak age - 13 to 14.
Approx. 80% - develop symptoms < 20 - Skoner et al., 2001
AR : Epidemiology
4.
5. • Decrease in infectious diseases is causally linked
to the increase in the incidence of allergic and
autoimmune diseases .
Hygiene Hypothesis
7. Atopy :
• Tendency to develop specific IgE in response to normally
innocuous environmental allergens
• Eg. allergic rhinoconjunctivitis, asthma, atopic dermatitis
& food allergies
• Multiple genetic loci on chromosomes 5q, 11q, 12q,
• Family history - major risk factor
• 13% -/- parent
• 29% +/- parent/sibling
• 47% +/+ parents
Atopy, Risk Factors, and Comorbid Disorders
8. Higher socioeconomic status
Polluted environments
Late entry into daycare
Kramer et al ., 1999
Heavy maternal smoking
during first year of life
Risk factors
13. Eosinophil
• Developed in bone marrow - IL3,IL5, GM-CSF
• Half life of 8-18 hrs – blood
Half life of several days - peripheral tissue
• Eosinophil migration ( into peripheral tissue)
• Toxic inflammatory mediators in eosinophil:
Major basic protein, eosinophil peroxidase, eosinophil
cationic protein
• Synthesize and release lipid mediators:
leukotriene C4
Pathophysiology
14. Irritation of free
nerve endings---- Itching and sneezing
Increased
mucus production ------ Rhinorrhoea
Vasodilation -------- Congestion
Increased
vascular permeability---- Oedema
How are the symptoms caused?
Pathophysiology
28. •Rapid, efficient & cost effective
•Antigens - representative of that patient may
encounter & geographically based.
Negative result usually requires no additional testing
Positive result requires further testing of other
antigens in the group or family.
Contain multiple antigens, (pollen, mold, weeds, dust
mite, animal dander)
Skin prick
29. Superficial skin reaction, does not penetrate dermis
Highly specific, sensitive, convenient and safe
Requires positive (histamine) and negative (saline) control
Method
Drop of standardized allergen extract-volar aspect of forearm-pricked into skin-
lancet
Positive control (histamine) ,-ve control (saline or diluent) –innoculated
Separate lancet -each test
Read -mean wheal diameter -15 mins
Reactions ->2 mm - <5 yrs
>3 mm- >5 yrs
+ve results - 2mm greater than –ve results
Skin prick
30. 0.01-0.05 mL - antigen
wheal and flare measured after 10-20 min
can be used to detect most low-degree atopies
does not permit accurate quantitation of sensitivity
Causes relatively minimal patient discomfort
Disadvantages
• higher risk of anaphylaxis
• longer time
• Possible false positive
Intradermal test
31. Modified method of IDT
Serially diluted antigen extracts used
-determine minimal amt of antigen -comparing size of
wheal
Principle -lowest concentration of antigen -produces -
wheal
1. first wheal more than 2 mm larger than negative control
wheal
2. followed by second wheal that is at least 2 mm larger than
preceding one.
Endpoint signifies -safe starting point for immunotherapy
Skin Endpoint Titration(SET)
32. Indications
Impracticality of skin testing
• Skin disorder, drug inhibition, uncooperatvie patients
Clarification of skin test results
• Bizarre or borderline reactions
Prevention of systemic reactions
• Prior history of anaphylactic reaction, severe asthma,
stinging hypersensitivity
In Vitro Testing
33. RAST (radioallergosorbent assay)
Allergen-specific IgE antibody testing
useful –
if percutaneous testing not practical
patients on-
- beta-blockers
- antihistamines (skin testing is unreliable)
- dermatographism, children cannot tolerate skin
testing
highly specific but not sensitive
(Agency for Healthcare Research and
Quality,2005 )
In vitro testing
34. • Useful - identifying common allergens (e.g., pet dander, dust
mites, pollen, common molds)
• less useful - identifying food, venom, or drug allergies.
• Allergen coupled to - paper disc and incubated with patients
serum
• Disc washed and radioactive anti-IgE added
• Gamma counters quantitates radioactivity
Radioimmunosorbant Assay
(RAST)
35. Involves an additional washing procedure in order to reduce
non-immunologically bound radioactivity
Increased sensitivity to RAST
MRT system divided into 5 classes from 1-5, each
representing approximately fivefold increase in amount of
serum specific IgE antibody present in sample.
Class Counts 0.1ml
Class 1 751-1600 1:500
Class 2 1601-3600 1:2500
Class 3 3601-8000 1:12500
Class 4 8001-18000 1: 62500
Class 5 18001-40000 1: 312,500
Modified RAST
(MRT)
36. Allergen introduced- nose
Reaction - measured
Rarely necessary
Performed when
- +ve history & –ive SPT
- prior to immunotherapy
Allergen –suitable form ( not containing
phenol or other irritants)
Nasal allergen challenge
39. • Exclusive breast feeding-3 month
• Total avoidance of environmental tobacco
smoke,passive smoking for children and prgnant
women
• In infant and pre school children,multifaceted
intervention to reduce early life exposure to
house dust mites
• For indivisuals exposed to occupational
agents,specific prevention measures eliminate or
reducing occupational exposure.
Recommendation for prevention of
allergy :: ARIA
40. • In patients with AR and /or asthma
sensitive to house dust mite allergens, do
not use single chemical or physical
preventive methods aimed at reducing
exposure to house dust mites or their
combination.
• In patients with allergy to indoor molds
animal dander ,avoid exposure to these
allergens at home.
• In pts with occupational asthma ,
immediate and total cessation of
exposure to occupational allergen
Recommendation for prevention of
allergy :: ARIA
41.
42. • Inhibit both early and late phases
• Counter effects of other mediators
• Fast-acting, to control the early phase
• Dosing-od or bd for compliance
• No side effects
• Manage all symptoms
• Intranasal administration
Jaci et al.,1999
The “Ideal” Drug For Allergic Rhinitis Should
HaveThe Following Features:
43. Single most effective agents
Improve all nasal symptoms-nasal
congestion, rhinorrhea, itching &
sneezing
Currently available INS -
beclomethasone dipropionate,
budesonide
fluticasone
flunisonide
mometasone
triamcinolone acetonide.
Intranasal corticosteroids
44. Local : nasal burning , stinging, dryness, and
epistaxis.
( 5% to 10% )
Local candidiasis, sometimes seen with inhaled
corticosteroids rarely seen with nasal
corticosteroids.
Systemic side effects :
minimal or no suppression hypothalamic-pituitary-adrenal axis
(Wilson et al.,1998)
Osteocalcin – (marker of bone turnover ) - unaffected
no increased likelihood of bone fracture - regardless of
dose. (Suissa et al.,2004)
Side effects of INS
45. Medication Adult dosage Child dosage Minimum age
FDA pregnancy/nursing
risk category
Beclomethasone
(Beclovent)
One or two sprays per
nostril twice daily
One or two sprays per
nostril twice daily
Six years C
Budesonide (Rhinocort) One to four sprays per
nostril daily
One or two sprays per
nostril daily
Six years C
Ciclesonide (Omnaris) Two sprays per nostril
daily
NA 12 years C
Flunisolide (formerly
Nasarel)
Two sprays per nostril
twice or three times
daily
Two sprays per nostril
twice daily
Six years C
Fluticasone furoate
(Veramyst)
Two sprays per nostril
daily
One spray per nostril
daily
Two years C
Fluticasone propionate
(Flonase)
Two sprays per nostril
daily
One or two sprays per
nostril daily
Four years C
Mometasone (Nasonex) Two sprays per nostril
daily
One spray per nostril
daily
Two years C
Triamcinolone (Nasacort) One or two sprays per
nostril daily
One or two sprays per
nostril daily
Six years C
46. • Acts - stabilizing H1-
receptor - smooth muscle
cells, nerve endings,
and glandular cells -
reduction in all
symptoms
• Only modest effect -
nasal congestion
H1-antihistamines
47. Medication Minimum age Adult dosage
Second generation
Acrivastine/pseudoephedrine* 12 years 8 mg four times daily
Azelastine (Astelin) Five years Two sprays per nostril twice daily
Cetirizine* (Zyrtec) Six months 5 to 10 mg daily
Desloratadine* (Clarinex) Six months 5 mg daily
Fexofenadine* (Allegra) Two years 180 mg daily or 60 mg twice daily
Levocetirizine (Xyzal) Six years 5 mg daily
Loratadine* (Claritin) Two years 10 mg daily
Olopatadine (Patanol) 12 years Two sprays per nostril twice daily
First generation
Brompheniramine Two years 12 to 24 mg twice daily
Chlorpheniramine* Two years 4 mg four times daily
Clemastine* (Tavist) Six years 1.34 mg twice or three times daily
Cyproheptadine Two years 4 mg three times daily
Diphenhydramine (Benadryl) Two years 25 to 50 mg four times daily
Hydroxyzine (Vistaril) All ages 25 mg four times daily
Promethazine (Phenergan) Two years 25 mg four times daily
Triprolidine (Tripohist) Six years 2.5 mg four times daily
Oral and Intranasal Antihistamines
49. action via a1 and a2 adrenoreceptors
reduction in blood flow - nasal vasculature - increased nasal patency
5 to 10 mins topically
30 mins - orally.
Nasal decongestion - last
8 hours - topical use
24 hours - extended-release oral decongestants
nasal congestion only affected
(Cohan RH et al.,1972)
monotherapy with vasoconstrictors - limited role
oral decongestants + antihistamine- all cardinal symptoms of AR -
targeted.
Decongestants
50. Cysteinyl-leukotrienes (cys-LT)
High concentrations LTC4 - in nasal secretions atopic
individuals after allergen challenge ( Wang D et al.,1995)
LTD4 -increase in nasal mucosal blood flow & nasal airway
resistance
(Bisgaard Het al.,1986)
Blockage of the LT
- 5-lipoxygenase (5-LO) inhibitors
-receptor blockade -cys-LT1 receptor
Zileuton -blocks the 5-LO pathway..
Antileukotrienes
51. Receptor antagonists-
Montelukast & zafirlukast.
Zafirlukast performed no better than placebo
- seasonal AR
( Pullerits T et al.,1999)
Other study - reduction in upper respiratory
responses to cat exposure
(Phipatanakul W et al.,2000)
Montelukast - clinical efficacy seasonal AR
(Chervinsky P et al.,2004)
Antileukotrienes
52. • Montelukast + loratadine -superior reducing day time nasal
symptoms in seasonal AR (Meltzer EO et al.,2000)
• Montelukast could be useful as monotherapy and in
combination with other classes of drugs
Int. Rev. Allergol. Clin. Immunol., 2011
• leukotriene antagonists do not appear more effective than
nonsedating antihistamines.
• less effective than INS
Ratner PH et al.,2003
Useful- concomitant mild persistent asthma and intermittent AR.
Antileukotrienes
53. Actions of Various Nasal Preparations in the
Treatment of Rhinitis
Nasal
Preparation
Sneezing Itching Rhinorrhoea Congestion
Antihistamines +++++ ++++ +++ 0
Anticholinergics 0 0 +++++ 0
Corticosteroids +++++ +++++ +++ +++
Decongestants 0 0 + +++++
Mast cell
stabiliser
+++++ +++ + 0
Antileukotrienes +++ ++ 0 ++++
54. Medical procedure that uses controlled exposure
to known allergens to reduce the severity of
allergic disease
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
Immunotherapy
55. Curtis (1900): immunize people with aqueous extract of
whole weeds
Dunbar(1903): immunize subjects who had grass-sensitive
hay fever with animal derived (horse and goose) grass pollen
antisera to subject’s nasal mucosa
Besredka and Steinhardt(1907): anaphylactic reaction
encountered during immunotherapy is due to immunizing too
rapidly or with too large dose of allergen
Noon and Cantab: introduced weight units for pollen doses
and quantization of individual sensitivity by in vivo testing.
Freeman and Koessler(1914): immunotherapy produced long
lasting results
Cooke(1915): Treatment by pollen immunization of 114
patients with hay fever and asthma.
Immunotherapy :History
56. Inclusion criteria:
IgE mediated disease
Inability to avoid allergen
Inadequecy of drug treatment
Lilited spectrum of allergen
Pts –risk & limitaion of tretment
Contraindications:
age < 5 yrs
use of beta-blockers
autoimmune dz.
pregnancy
uncontrolled asthma FEV1 < 70%
Immunotherapy
57. Gradual increase of allergen-specific IgG antibodies --
especially IgG4 subclasses (blocking antibody)
• intercept and neutralize allergen before it bound to cell-surface IgE
• form IgG-antigen-IgE complex and bind to the IgG receptor resulting
co-aggregation with the IgE receptor and inhibition of IgE receptor
triggering
decreased allergen-specific IgE antibodies
increase IgA and IgM antigen-specific B lymphocytes
• May limit antigen penetration into the body from mucosa
Deviation fromTh2 toTh1 cell
Immunotherapy
Mechanism:
58. • Durhan et al.:
• Randomized, placebo-controlled, double-
blind study
• Patients (32) with allergy to timothy grass-
pollen extract received 3 years of
immunotherapy treatment
• Patients then randomized to continue with
the immunotherapy or to receive placebo
• 15 matched patients never received
immunotherapy as control group
• Presence of symptoms and need for rescue
medication were measured after 3 years
Long term efficacy of
immunotherapy
59. • No significant difference in symptom scores and
use of rescue medication between two
immunotherapy groups, and were lower than
control group
• No difference in the late skin responses (size of
swelling, number of infiltrating T cells, cells
containing IL-4 mRNA) between two
immunotherapy groups, and significantly lower
than control group
• Immunotherapy for grass-pollen allergy for three
to four years induces prolonged clinical remission
accompanied by a persistent alteration in
immunologic reactivity
Long term efficacy of
immunotherapy
60. may prevent progression of rhinitis to asthma in
children
• Preventive AllergyTreatment Study:
• 205 children from 6 pediatric allergy centers in northern Europe
aged 6-14 years with grass or birch pollen allergy
• randomly assigned either to receive specific immunotherapy for 3
years or to a control group
• The children who were treated with immunotherapy had
significantly fewer asthma symptoms after 3 years as evaluated by
clinical diagnosis
may prevent onset of new sensitization in allergic
patients
Advantage of immunotherapy
61. • Proven allergy with skin test or RAST
• With allergic symptoms that are significant to
the patient
• 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
Patient selection
62. Subcutaneous immunotherapy - only approved route of
administration in USA
Subcutaneous immunotherapy - involves a weekly
subcutaneous injection of an extract of the allergen, in
solution, in increasing doses until a standard maintenance
dose is reached.
This dose is then injected subcutaneously on a regular basis
(at intervals of approximately 20 days) for not less than 3
years for perennial allergens.
Short term immunotherapy does not affect the cytokine
profile and do not have long-term efficacy after
discontinuation
start at an earlier age, so that adverse changes to the
immune system can be prevented before they become
irreversible
Immunotherapy
63. Considerations in writing an allergy extract (vaccine) prescription are:
• decision as to which allergen extracts to include
• maintenance doses which have been proven to be clinically effective
• potency of the allergen extracts available
• patterns of cross-reactivity and
• deleterious effects of some allergen extracts on others with which they may be mixed.
Writing an allergen extract
(vaccine) prescription
64. Clinical experience indicates that the 1:1000 v/v
dilution of the maintenance vial is generally a safe
starting concentration
Skin endpoint titration can also be used to
determine starting dose, based on dilution which
elicited positive reaction
Patients may also be prick skin tested with each
dilution of extract mix and immunotherapy
commenced with the most dilute concentration
that yields a positive prick skin test.
Starting Concentration
65. Wilson et al.:
• 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
• whether sublingual therapy equals the efficacy of
subcutaneous immunotherapy is not clear
Sublingual immunotherapy
widely used and investigated in Europe since late 1980’s
keep the extract under the tongue for a couple of minutes and then swallow
it
dose of allergen is greater than subcutaneous immunotherapy (about 3-300
times higher)
Efficacy of sublingual immunotherapy
67. Double blind placebo-controlled study of ragweed
immunotherapy
Observed that SCIT alone induced allergen-
specific IgG4 that partially blocked binding of
allergen-IgE complexes to cells
This binding was completely blocked with the
addition of omalizumab
Immunotherapy with Omalizumab
Klunker S, Saggar LR, et al. Combination treatment with omalizumab
and rush immunotherapy for ragweed induced allergic rhinitis: inhibition
of IgE facilitated allegen binding. J AllergyClin Immunol 2007; 120:688-695.
68. Constant symptoms of profuse , clear rhinorrhea ,
nasal congestion without correlation to specific
antigen exposure or signs of atopy.
• ALSO CALLED noninfectious nonallergic rhinitis or idiopathic rhinitis , is a
chronic nasal dysfunction characterized by nasal hyperreactivity, i.e., nasal
blockage, rhinorrhea, and sneezing in response to nonallergic stimuli such as
•emotional factors
• exposure to cold air
• sudden temperature change
•humidity
• tobacco smoke
• or irritating body sprays and cosmetics
•Segal et al., in a recent report, studied previous nasal trauma as a
causative factor.
VASOMOTOR RHINITIS
69. Several mechanisms have been postulated to explain
the pathophysiology of idiopathic rhinitis
(i) increased permeability of the nasal epithelium
(ii) non-IgE-mediated inflammatory responses;
(iii) neurogenic responses are the most plausible
The classical theory is that vasomotor rhinitis is
caused by autonomic imbalance:
• Underactivity of the sympathetic nervous system
Overactivity of the parasympathetic nervous system
(singer et al).
Mechanisms of vasomotor rhinitis
70. Other theories
increase in vasoactive peptides released from mast cells.
• histamine,
• leukotrienes,
• prostaglandins,
• vasoactive intestinal polypeptide,
• kinins
but release of these peptides is non-IgE mediated, as it
is in allergic rhinitis
Mechanisms of vasomotor rhinitis
71. variable presentation.
Most patients - older
sometimes -seasonal pattern.
Patients present with
rhinorrhea (thick or scanty)
frontal headaches
congested turbinates
but usually no pruritis.
Rates of anxiety and depression are higher in women
with vasomotor rhinitis than in healthy women without
rhinitis
(Addolorato G et al)
Clinical presentation :
72. Vasomotor rhinitis - a diagnosis of exclusion i.e., absence of
• Infection
• Exposure to drugs,
• Significant anatomical disorder of the nose
• Hormonal change
• Negative response to skin prick test,
• Normal serum specific Ig
Lal D and Corey JP. Vasomotor rhinitis update.
The rhinomanometric exercise test
Acta Otorhinolaryngology
Diagnostic approach
73. If the irritant is known, the best treatment is prevention,
Pharmacological: Surgical
Antihistamines Triamcinoline injection
Ant-cholinergic agents Electrical cautrey
Topical steroids Cryosurgery
Decongestants Laser
Vidian neurectomy
Treatment
74. • Topical anticholinergics should be used for rhinorrhea caused
by vasomotor rhinitis.
• Azelastine (Astelin) may be used for vasomotor rhinitis
associated with rhinorrhea, sneezing, postnasal drip, and nasal
congestion.
• Topical corticosteroids may be used for vasomotor rhinitis
associated with nasal obstruction and congestion.
• Cromolyn sodium (Intal) may be used for vasomotor rhinitis
associated with sneezing and congestion in patients older than
two years.
A = consistent, good-quality, patient-oriented evidence; B = inconsistent or limited-quality, patient-oriented evidence; C = consensus, disease-oriented
evidence, usual practice, expert opinion, or case series
American Family Physician
75.
76. The effect of intranasal injection of botulinum toxin A on the
symptoms of vasomotor rhinitis
Intranasal injection of BTX-A is a highly effective, safe, and
simple treatment modality with a long-lasting effect for patients
with VMR. Botulinum toxin A may be a good alternative especially
for the treatment of resistant VMR cases.
Cengiz O zcan, et al
77. Vidius (1509) 1st –identified
Sectioning of GSPN as a treatment for VMR -1st proposed by
Zeilgelmann .
VIDIAN NERVE
78. CRYOSURGERY ON POSTGANGLIONIC FIBERS
(POSTERIOR NASAL BRANCHES) OF THE PTERYGOPALATINE
GANGLION FOR VASOMOTOR RHINITIS
Operative technique
79. • Incision –hard palate
• Mucoperiosteal dissected till
palatal aponeurosis is visible
• Soft palate incised from post
end of hard palate-nasopharynx
• L Shaped incision long limb-just above
the tubal elevation, short limb- b/w post. &
lat. Wall of nasopharynx
• Mucosal elevation-exposed med pterygoid
plate-drilled-canal opened-nerve cut &
cauterized
Transpalatal approach
80. • Using operative microscope
• Incision-sup surface of inf turbinate-post end
of middle turbinate
• Mucoperiosteum elevated
• Ethmoidal creast identified
• Exposing sphenopalatine
foramen-ptergoid canal identified
• Nerve cauterized.
Transnasal approach
81. Step1 –lateralization of middle
turbinate
Step2-perforation of ant wall of
sphenoid sinus(using elevator)- opening
over the ant. Face of sphenoidal sinus
is widened till vidian canal is
identified.
Step3-wall of vidian canal is
perforated –nerve is severed.
Endoscopic intrasphenoidal
82. • Incision –curved incision given in middle
meatus(post end of sup margin of inf
turbinate to horizontal part of ground
lamella)
• Mucoperiosteal elevated
• The sphenopalatine foramen and sup
portion of perpendicular plate of palatine
bone - exposed
• Post. Sup. And post. Inf. Nasal nerve
identified and sectioned.
Endoscopic post. Nasal neurectomy
83. • Palpate the lateral nasal wall behind the uncinate
and above the insertion of the inf turbinate
• Identify the soft membranous part of post
frontanelle
• Identified palatine bone
• C shaped incision
• Mucoperiosteal flap raised
• Dissection is continued till the ant. Face of sphenoid
sinus
• Post. Rim of sphenopalatine foramen widened
• Vidian canal identified—nerve exposed--cut
Endoscopic vidian neurectomy