Dr MadanJr ENT

ALLERGIC RHINITIS & VMRAETIOLOGY, PATHOGENESIS, CLINICAL FEATURE TREATMENT AND ROLE OF IMMUNOTHERAPY

• “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

• 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

• Decrease in infectious diseases is causally linked to the increase in the incidence of allergic and autoimmune diseases .

Hygiene Hypothesis

l Genetic predisposition

l Environment changes

l Hygiene hypothesis

What are the causes?

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

Higher socioeconomic status

Polluted environments

Late entry into daycare

Kramer et al ., 1999

Heavy maternal smoking during first year of life

Risk factors

Pathophysiology

Pathophysiology

From: Immunology a short course, 1996

Pathophysiology

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

Irritation of freenerve endings---- Itching and sneezing

Increasedmucus production ------ Rhinorrhoea

Vasodilation -------- Congestion

Increasedvascular permeability---- Oedema

How are the symptoms caused?

Pathophysiology

©

Approach to the pt :

Approach to the pt :

Seasonal

Perennial

Types of Allergic Rhinitis

ARIA Classification:

Physical examination

Adenoid facies :

LungsWheezing

Persistent coughing

Other areasStigmata of atopic diseases with nasal symptoms• atopic eczema, asthma

Others -

DIFFERENTIAL DIAGNOSIS

Take a moment to consider your differential diagnosis

NON-ALLERGIC RHINITIS• VASOMOTOR• COLD AIR INDUCED• NARESINFECTIOUS RHINITISGRANULOMATOUS RHINITISDRUG INDUCED RHINITIS - OCP,HYDRALAZINE HYDROCHLORIDE,TOPICAL DECONGESTANTS,RESERPINE DERIVATIVE

MECHANICAL OBSTRUCTION- SEPTAL DEVIATION,FB,CHOANAL ATRESIA,ADENOID HYPERTROPHYNEOPLASTIC RHINITIS- BENIGN, MALIGNANT

• Nasal Cytology

• Skin Prick tests

• In vitro tests

Allergy Testing

•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

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

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

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)

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

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

• 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)

Involves an additional washing procedure in order to reduce non-immunologically bound radioactivity

Increased sensitivity to RASTMRT 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 0.1mlClass 1 751-1600 1:500Class 2 1601-3600 1:2500Class 3 3601-8000 1:12500Class 4 8001-18000 1: 62500Class 5 18001-40000 1: 312,500

Modified RAST(MRT)

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

Initially- Placebo ,diluents 0f allergen –employed

Allergen-gradually increasing concentration –monitoring URT & LRT symptoms

Subjective –symptom scores, VASs

Objective –sneeze count, nasal inspiratory peak flow , rhinomanometry , acousrtic rhinometry , spirometry ,pulmonary peak flow

BUT…..

Time consuming

Excessive lab facilities

Trained staff

Resuscitation equipment

Nasal allergen challenge

• 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

• 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

• 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 Have The Following Features:

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

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

Medication Adult dosage Child dosage Minimum ageFDA 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

• Acts - stabilizing H1-receptor - smooth muscle cells, nerve endings, and glandular cells - reduction in all symptoms

• Only modest effect - nasal congestion

H1-antihistamines

Medication Minimum age Adult dosageSecond 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

Topical and oral form.

Topical vasoconstrictor:

-catecholamine (eg, phenylephrine)

-imidazoline (eg, oxymetazoline)

oral vasocontrictor-

-phenylephrine

- pseudoephedrine.

Decongestants

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

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

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

• 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

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 ++++

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

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

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

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 from Th2 to Th1 cell

Immunotherapy Mechanism:

• 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

• 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

may prevent progression of rhinitis to asthma in children • Preventive Allergy Treatment 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

• 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

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

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

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

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 immunotherapywidely 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

Updosing phase-

weekly inj -8 to 16 wks

Maintainance phase-

4- 8 wkly intervals-3-5yrs

Hospital basis

Observation -60 min

Protocols

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 Allergy Clin Immunol 2007; 120:688-695.

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

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

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

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 :

 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

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

• 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

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

Vidius (1509) 1st –identified

Sectioning of GSPN as a treatment for VMR -1st proposed by Zeilgelmann .

VIDIAN NERVE

CRYOSURGERY ON POSTGANGLIONIC FIBERS(POSTERIOR NASAL BRANCHES) OF THE PTERYGOPALATINEGANGLION FOR VASOMOTOR RHINITIS

Operative technique

• 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

• 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

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

• 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

• 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