Coass II-Allergy Rhinitis

7/24/2019 Coass II-Allergy Rhinitis

1/77

2003 The American Academy of Otolaryngology Head and Neck Surgery Foundation2003 The American Academy of Otolaryngology Head and Neck Surgery Foundation

Allergic RhinitisAllergic RhinitisThird EditionThird Edition

James A. Hadley, M.D. andJames A. Hadley, M.D. andJ. David Osguthorpe, M.D.J. David Osguthorpe, M.D.


2/77


Nasal Airway InsufficiencyNasal Airway Insufficiency(the stuffy nose)(the stuffy nose)

ALLERGYALLERGY(medically reported as 1 ! ""# of population)(medically reported as 1 ! ""# of population) ANAT$%I& $'TR&TI$NANAT$%I& $'TR&TI$N(septum* tur+inate)(septum* tur+inate) R,IN$INITIR,IN$INITI (self reported +y 1- !1./0# of population)(self reported +y 1- !1./0# of population)

NON-ALLERGIC RHINITISNON-ALLERGIC RHINITIS(asomotor* gustatory* etc/)(asomotor* gustatory* etc/) %E2I&ATI$N I2E E33E&T%E2I&ATI$N I2E E33E&T(rhinitis medicamentosa*(rhinitis medicamentosa*

anti!,TN* +irth control pills* estrogen* etc/)anti!,TN* +irth control pills* estrogen* etc/)

4RE5NAN&6 or $T,ER EN2$&RINE4RE5NAN&6 or $T,ER EN2$&RINE

$R&E* 37I2 RETENTI$N$R&E* 37I2 RETENTI$N NE$47A%* 3$REI5N '$26* ET&/NE$47A%* 3$REI5N '$26* ET&/


3/77


Nasal Insufficienty can e multifactorial.Nasal Insufficienty can e multifactorial.NasalNasal

insufficiencyinsufficiency

can +ecan +emultifactorialmultifactorial

This cigarette

smo8er has aseptal deiation*tur+inatehypertrophyfrom allergies*polyps* 9rhinosinusitis/


4/77


Allergic and Non! Allergic RhinitisAllergic and Non! Allergic Rhinitis

This educational slide seriesThis educational slide series

will reiew thewill reiew the

pathophysiology* impact*pathophysiology* impact*

diagnosis and managementdiagnosis and managementscenarios of +oth allergic andscenarios of +oth allergic and

non!allergic rhinitis/non!allergic rhinitis/

A summary of theA summary of the

otolaryngolgist:s perspectieotolaryngolgist:s perspectieand treatment paradigms/and treatment paradigms/


5/77


Impact of Allergic RhinitisImpact of Allergic Rhinitis

;;thth

most prealent chronic* 9 most commonmost prealent chronic* 9 most commonrespiratory* disease (most prealent chronicrespiratory* disease (most prealent chronic

condition in those < 1= y>o)condition in those < 1= y>o)

"/0# physician office isits* common reason for"/0# physician office isits* common reason for

+oth $T& 9 physician prescriptions+oth $T& 9 physician prescriptions Diminished QOLDiminished QOL(irrita+ility* fatigue* sleep(irrita+ility* fatigue* sleep

distur+ance* depression)distur+ance* depression)

2irect costs to economy of appro?imately @/02irect costs to economy of appro?imately @/0

+illion>year* plus !+illion>year* plus ! ./= million lost wor8 9 school days annually./= million lost wor8 9 school days annually


6/77


Allergic Rhinitis B Associated 2iseasesAllergic Rhinitis B Associated 2iseases

AllergicRhinitis

OtitisOtitisMediaMedia

AsthmaAsthma

Laryngitis,

Pharyngitis Rhinosinusitis

Chronic

Rhinitis


7/77


&omplications of Allergic Rhinitis&omplications of Allergic Rhinitis

Rhinosinusitis* Nasal 4olypsRhinosinusitis* Nasal 4olyps

4haryngitis* 7aryngitis4haryngitis* 7aryngitis

$titis %edia* $titis E?terna$titis %edia* $titis E?terna

&onCunctiitis&onCunctiitis E?acer+ation of Asthma* 'ronchitis* Dertigo*E?acer+ation of Asthma* 'ronchitis* Dertigo*

%igraine* Ecema%igraine* Ecema

Impaired $lfaction > Taste* leep Apnea*Impaired $lfaction > Taste* leep Apnea*

3acial 5rowth A+normalities in3acial 5rowth A+normalities in &hildren&hildren(all(all

from nasal o+struction)from nasal o+struction)


8/77


Allergic RhinitisAllergic Rhinitis

Provoked by e!os"re #o $n#i%ensProvoked by e!os"re #o $n#i%ens (allergens) in the enironment and food(allergens) in the enironment and food

Sym!#oms&Sym!#oms&

! Nasal congestion with nasal mucosal edema orNasal congestion with nasal mucosal edema or

o+struction (mouth +reathing* midfacialo+struction (mouth +reathing* midfacialfullness > pressure or headache/)fullness > pressure or headache/)

! neeing* nasal* conCunctial and>or palatalneeing* nasal* conCunctial and>or palatal

pruritispruritis

! Fatery rhinorrhea* post nasal drip* lacrimationFatery rhinorrhea* post nasal drip* lacrimation! 2iminished sense of smell* Eustachian tu+e2iminished sense of smell* Eustachian tu+e

dysfunctiondysfunction


9/77


2efinition of Allergy2efinition of Allergy

'on Pir("e# )*+,'on Pir("e# )*+,Aer%yAer%yAn $#ered re$.#ivi#y #o $ /orei%n s"bs#$n.eAn $#ered re$.#ivi#y #o $ /orei%n s"bs#$n.e$/#er !rior e!os"re #o #he s$me m$#eri$0$/#er !rior e!os"re #o #he s$me m$#eri$0

Allergy 9 ,ypersensitiity are usedAllergy 9 ,ypersensitiity are usedinterchangea+ly to descri+e an aderseinterchangea+ly to descri+e an aderseclinical reaction to an enironmental agentclinical reaction to an enironmental agentcaused +y an immunological reactioncaused +y an immunological reaction(Antigen!Anti+ody reaction)/(Antigen!Anti+ody reaction)/


10/77


,ypersensitiity Reactions,ypersensitiity Reactions(Allergic Rhinitis is primarily a Type I*(Allergic Rhinitis is primarily a Type I*

IgE mediated reaction)IgE mediated reaction)

Ty!e ITy!e I Immediate (Immediate ($er%i. rhini#is$er%i. rhini#is* asthma** asthma*

immediate onset food reactions)immediate onset food reactions)

Type II &ytoto?icType II &ytoto?ic (hemolytic anemia* ,ashimoto:s)(hemolytic anemia* ,ashimoto:s)

Type III Immune &omple?Type III Immune &omple? (serum sic8nesss*(serum sic8nesss*

delayed onset food reactions*delayed onset food reactions*

glomerulonephritis)glomerulonephritis)

Type ID 2elayed* &ell %ediatedType ID 2elayed* &ell %ediated (T'* poison iy)(T'* poison iy)

Type D timulating Anti+ody ReactionType D timulating Anti+ody Reaction (5raes:)(5raes:)

Type DI Anti+ody 2ependent &ell &yto?icityType DI Anti+ody 2ependent &ell &yto?icity

(transplant reCection)(transplant reCection)


11/77


2efinitions Releant to Allergic Rhinitis2efinitions Releant to Allergic Rhinitis

,ypersensitiity,ypersensitiity! A heightened or e?aggerated immune responseA heightened or e?aggerated immune response

that deelops after G1 e?posure to a specificthat deelops after G1 e?posure to a specific

antigen/antigen/

Allergen (Antigen)BAllergen (Antigen)B! A foreign su+stance that when introduced into theA foreign su+stance that when introduced into the

+ody elicits a specific immunologic response/+ody elicits a specific immunologic response/

Anti+odyBAnti+odyB! A protein (immunoglo+ulin) that selectiely +indsA protein (immunoglo+ulin) that selectiely +inds

to a specific allergen/to a specific allergen/


12/77


1/ ,ost sensitiation to allergen

"/ IgE production +y host

./ %ast cell sensitiation

/ Allergen proocation +y furthere?posure after sensitiing eent

0/ %ediator releaseB

His#$mine1 kinins1 e"ko#rienes1 .y#okines

;/ End!organ response

4athophysiology of Allergic 2isease4athophysiology of Allergic 2isease


13/77


4athophysiology of Allergic4athophysiology of Allergic

InflammationB ensitiationInflammationB ensitiation

4hase 1 B ensitiation4hase 1 B ensitiation

Antigen!presentingcell

&2T cell

' cell

IgE anti+odies

Allergens

4rocessedallergens

4lasma cell

Naclerio, "M. Ne# $ngl J Med %&&%'()*+ -/&


14/77


4athophysiology of Allergic4athophysiology of Allergic

InflammationB &linical 2iseaseInflammationB &linical 2isease

4hase " B &linical 2isease4hase " B &linical 2iseaseEarly

Inflammation

Allergens

0nee1ing

"hinorrhea

2ongestion

Mast

cell

Ig$ antiodies

Mediator release

3loodvessels

Nerves

4lands

7ateInflammation

2ellularinfiltration

$osinophils

3asophils

Monocytes

5ymphocytes

"esolution

2omplications

Irreversiledisease 678

7ate!phasereaction

4riming

,yper!responsieness


15/77


%ast &ells > 'asophils and%ast &ells > 'asophils and

Inflammatory &ascadeInflammatory &ascade

NucleusNucleusNucleusNucleus9999

PreformedPreformed

MediatorsMediators-Histamine-Histamine

-Heparin-Heparin

-Tryptase (Mast Cells)-Tryptase (Mast Cells)

CytokinesCytokines-IL-4,5,6,8-IL-4,5,6,8

LipidLipid

MediatorsMediators-PGs-PGs

-LTs-LTs

AntigenAntigen


16/77


&hemical %ediators of Allergic* and ome&hemical %ediators of Allergic* and ome

Non!Allergic* RhinitisNon!Allergic* Rhinitis(principally from %ast cells 9 'asophils)(principally from %ast cells 9 'asophils)

4re!formed (stored)4re!formed (stored)

mediatorsmediators

! ,istamine,istamine! HininsHinins

! ,eparin,eparin

! 4latelet actiating4latelet actiatingfactor (4A3)factor (4A3)

Newly formed mediatorsNewly formed mediators(created +y 9 after reaction)(created +y 9 after reaction)

! 7eu8otrienes7eu8otrienes 7T'* 7T&* 7T27T'* 7T&* 7T2

! &yto8ines&yto8ines E&3!A*E&3!A*

! 4rostaglandins4rostaglandins 452"452"

! Interleu8insInterleu8ins

' i I l


17/77


'asic ImmunologyB'asic ImmunologyB

ensitiation s/ u+seuentensitiation s/ u+seuent

E?posureE?posure

Mast CellB-cell Degranulation

Sensitization IgE presentation IgE bridgingSensitization IgE presentation IgE bridging

Macrophage

Antigen

T-cell

TH2

Cytokines

I

II

IgE


18/77


Mast Cell Mediators

Early 4hase Reaction 7ate 4hase Reaction(ma?imum 1-!.- minutes) (ma?imum at 1-!1" hours)4ruritis* neeing Infiltration with Eosinophilsmooth muscle contraction 3i+rin deposition3lush* Dascular lea8age with Infiltration with %onocytesRhinorrhea Tissue destruction

Nasal congestion%ucous ecretion

Atg

&onseuences of %ediator Release&onseuences of %ediator Release


19/77


Nasal Response to Inhaled AllergenNasal Response to Inhaled Allergen

Time in Hours from Initial

Challenge

Early Phase

Response

Late Phase

Response

y

m

p

to

m

s


20/77


Types of Rhinitis ! 1Types of Rhinitis ! 1

Se$son$ $er%i. rhini#isSe$son$ $er%i. rhini#is(classic hayfeer with(classic hayfeer withspring* summer 9>or fall symptoms)spring* summer 9>or fall symptoms) Perenni$ $er%i. rhini#isPerenni$ $er%i. rhini#is(mite* mold*(mite* mold*

coc8roach* animal dander)coc8roach* animal dander)

Infectious rhinitisInfectious rhinitis(irus* +acteria* fungi)(irus* +acteria* fungi) $ccupational rhinitis$ccupational rhinitis(late?)(late?) &hemical > irritatie rhinitis&hemical > irritatie rhinitis(perfumes*(perfumes*

strong odors* fine particles)strong odors* fine particles)

Anatomic rhinitisAnatomic rhinitis(nasal drainage o+struction(nasal drainage o+struction+y septum* etc/)+y septum* etc/)


21/77


Tur+inate ,ypertrophy>Rhinitis of 4regnancyTur+inate ,ypertrophy>Rhinitis of 4regnancy


22/77


Types of Rhinitis ! "Types of Rhinitis ! "

'$somo#or rhini#is'$somo#or rhini#is(temperature ariation(temperature ariationinduced* either inhaled or with food inta8e)induced* either inhaled or with food inta8e)

Non!allergic rhinitis with eosinophiliaNon!allergic rhinitis with eosinophilia

%edication!induced rhinitis%edication!induced rhinitis (rhinitis(rhinitis

medicamentosa* oral contracepties* anti!medicamentosa* oral contracepties* anti!hypertensies)hypertensies)

,ormonal rhinitis,ormonal rhinitis (pregnancy* menopause*(pregnancy* menopause*hypothyroidism)hypothyroidism)

Atrophic rhinitisAtrophic rhinitis (ageing* surgery* infection)(ageing* surgery* infection)

5ustatory rhinitis5ustatory rhinitis(food allergy induced)(food allergy induced)


23/77


ARIA &lassification 9 Allergic RhinitisARIA &lassification 9 Allergic Rhinitis

%oderateJseereOne or more i#ems

A+normal sleep

Impairment of daily

actiities* sport* leisure A+normal wor8 and school

Trou+lesome symptoms

%oderateJseereOne or more i#ems

A+normal sleep

Impairment of dailyactiities* sport* leisure

A+normal wor8 and school

Trou+lesome symptoms

4ersistent G days per wee8

and G wee8s

4ersistent G days per wee8

and G wee8s

%ild Normal sleep9 no impairment of daily

actiities* sport* leisure

9 normal wor8 and school9 no trou+lesome symptoms

%ild Normal sleep9 no impairment of daily

actiities* sport* leisure

9 normal wor8 and school

9 no trou+lesome symptoms

Intermittent ymptoms < days per wee8

or ymptoms < wee8s

Intermittent ymptoms < days per wee8

or ymptoms < wee8s


24/77


ymptoms of Allergic Rhinitisymptoms of Allergic Rhinitis

4roo8ed +y e?posure to Antigens4roo8ed +y e?posure to Antigens (in atopic conte?t*(in atopic conte?t*called Allergens)called Allergens)in enironment 9 foodin enironment 9 food

&ommon ymptomsB&ommon ymptomsB

! Nasal* conCunctial 9>or palatal pruritisNasal* conCunctial 9>or palatal pruritis

!neeing* watery rhinorrhea* post nasal drip*neeing* watery rhinorrhea* post nasal drip*lacrimationlacrimation

! %ucosal edema with nasal congestion >%ucosal edema with nasal congestion >o+structiono+struction (mouth +reathing* sleep distur+ances)(mouth +reathing* sleep distur+ances)**sinus ostial 9>or eustachian tu+e dysfunctionsinus ostial 9>or eustachian tu+e dysfunction

(midfacial pressure>pain* headache* ear pressure 9(midfacial pressure>pain* headache* ear pressure 9occasional mild diyness)occasional mild diyness)* 9 diminished olfaction* 9 diminished olfaction


25/77


2iagnosis and the Allergic 4atient2iagnosis and the Allergic 4atient

2iagnosis +ased onB2iagnosis +ased onB

1/ ,istory1/ ,istory

"/ 4hysical E?amination"/ 4hysical E?amination

././7a+oratory 9>or 8in Testing7a+oratory 9>or 8in TestingNoteB K 1 9 K" suffice for initiation ofNoteB K 1 9 K" suffice for initiation of

Enironmental %easures 9 4harmacotherapy*Enironmental %easures 9 4harmacotherapy*and may +e all that is necessary in mild toand may +e all that is necessary in mild to

moderate casesL K. affords definitie diagnosismoderate casesL K. affords definitie diagnosis9 is reuired prior to Immunotherapy9 is reuired prior to Immunotherapy


26/77


Allergies 9 4ast %edical ,istoryAllergies 9 4ast %edical ,istory

&hildhood allergy > asthma&hildhood allergy > asthma

Recurrent $%* recurrentRecurrent $%* recurrent

acute or chronic Racute or chronic R

EcemaEcema &olic > formula intolerance&olic > formula intolerance

Anaphylactic reaction (foodAnaphylactic reaction (food

or drug)or drug)

easonal colds (spring*easonal colds (spring*fall)fall)

urgeryurgery

T 9>or AT 9>or A

4 E Tu+es4 E Tu+es

inusinus $T& or R?$T& or R?

medications withmedications with

anti!allergy* coldanti!allergy* cold

or decongestantor decongestanteffectseffects


27/77


Allergies 9 3amily ,istoryAllergies 9 3amily ,istory

&hance ofhaing

$#o!y+ased onfamilyhistory


28/77


4hysical E?amination of Allergy 4atient4hysical E?amination of Allergy 4atient

EyesB conCunctiitis*EyesB conCunctiitis* Dennie2s ines1 3shinersDennie2s ines1 3shiners

EarsB otitis media or e?terna* retractedEarsB otitis media or e?terna* retracted

tympanic mem+rane from ET dysfunctiontympanic mem+rane from ET dysfunction

NoseB +oggy > pale nasal mucosa* clear > thinNoseB +oggy > pale nasal mucosa* clear > thinmucoid rhinitis* tur+inate hypertrophy* polyps*mucoid rhinitis* tur+inate hypertrophy* polyps*

transerse nasal crease fromtranserse nasal crease from 3$er%i. s$"#e03$er%i. s$"#e0

ThroatB prominent lymphoid patchesThroatB prominent lymphoid patches

(co++lestoning)* lateral pharyngeal +ands(co++lestoning)* lateral pharyngeal +ands


29/77


30/77


R MR Mtur+inate congestion 9 hypertrophy fromtur+inate congestion 9 hypertrophy from

allergiesLallergiesL 7 M allergic conCunctiitis7 M allergic conCunctiitis

!

R L


31/77


4osterior 4haryngeal &o++lestoning (su+mucosal4osterior 4haryngeal &o++lestoning (su+mucosal

lymphoid hyperplasia from chronic post!nasal driplymphoid hyperplasia from chronic post!nasal drip

of inhalant allergies)of inhalant allergies)


32/77


4hysical E?amination4hysical E?amination

of Allergy 4atientof Allergy 4atient

2entalB crowded teeth* high arched palate2entalB crowded teeth* high arched palate

Nasopharyn?B hypertrophic adenoidsNasopharyn?B hypertrophic adenoids (adenoid facies)* lateral pharyngeal +ands(adenoid facies)* lateral pharyngeal +ands

7aryn?B edematous > polypoid ocal cords7aryn?B edematous > polypoid ocal cords

7ungsB si+ilant rales* wheeing suggestie of7ungsB si+ilant rales* wheeing suggestie of

+ronchospasm+ronchospasm

8inB ecema or other pruritic rashes8inB ecema or other pruritic rashes(especially if food allergic)(especially if food allergic)


33/77


7 M7 MRash from 'irch &ontaining hampooLRash from 'irch &ontaining hampooL

R MR MAtopic Ecema from 3ood ensitiitiesAtopic Ecema from 3ood ensitiities

L R


34/77


IgE testingSkin 3In vivo0 4!ri.k or in#r$derm$ #es#s)

7a+oratory In itro antigen specific assay(radioallergosor+ent > RAT Test or enyme lin8ed

immunosor+ent > E7IA Test) $ther 7a+oratory testingB

!Eosinophil count (also may +e eleated in asthma*NARE* parasitic infection* etc/)

!Nasal cytology 2ietary Elimination and &hallenge 3eeding tests

Testing for Allergic RhinitisTesting for Allergic Rhinitis


35/77


In Dio or In Ditro Allergy creensIn Dio or In Ditro Allergy creens

Test 'attery of = ! 1" common Allergens in patient:sTest 'attery of = ! 1" common Allergens in patient:sgeographic region is ;# efficient 9 /"#geographic region is ;# efficient 9 /"#sensitie in detecting those with clinicallysensitie in detecting those with clinicallysignificant sensitiitiessignificant sensitiities(unless there is an unusual(unless there is an unusualor occupational e?posure* e/g/ late? in health careor occupational e?posure* e/g/ late? in health care

wor8er* mice in la+oratory wor8er)wor8er* mice in la+oratory wor8er)

E?ample of common inhalant screenB " trees* 1!"E?ample of common inhalant screenB " trees* 1!"weeds* 1!" grasses* 1 mite* coc8roach* " molds*weeds* 1!" grasses* 1 mite* coc8roach* " molds*cat dandercat dander

In children with ecema* colic* etc/* common foodsIn children with ecema* colic* etc/* common foodscan +e added to screen* such as mil8* soy+ean*can +e added to screen* such as mil8* soy+ean*peanut* egg* wheat* cornpeanut* egg* wheat* corn


36/77


Nasal &ytogramNasal &ytogram// mucous* epithelial cells and some +acteria*mucous* epithelial cells and some +acteria*with leu8ocytes (9 more +acteria) in infection* 9 eosinophils in allergywith leu8ocytes (9 more +acteria) in infection* 9 eosinophils in allergy

(most of the time)(most of the time)


37/77


&linical Approach to the Allergic 4atient&linical Approach to the Allergic 4atient

C$ssi. Q"$r#e# o/ Tre$#men# A!!ro$.hes&C$ssi. Q"$r#e# o/ Tre$#men# A!!ro$.hes&

11/ Aoidance 9 Enironmental %easures/ Aoidance 9 Enironmental %easures

""/ &ounseling of 4atient 9 3amily/ &ounseling of 4atient 9 3amily

(home* ocation* aocation* school(home* ocation* aocation* school))

./ 4hysical fitness./ 4hysical fitness/ 4harmacotherapy (e/g/* steroids* antihistamines)/ 4harmacotherapy (e/g/* steroids* antihistamines)

00// Eradicate comor+idityEradicate comor+idity

;/;/ ImmunotherapyImmunotherapy

Oif warranted +y s8in or in itro testing that confirms IgE toOif warranted +y s8in or in itro testing that confirms IgE tooffending Allergens* plus inadeuate (or unrealistic) controloffending Allergens* plus inadeuate (or unrealistic) control

+y +oth K" 9 K .P+y +oth K" 9 K .P


38/77


2iagnosis and Treatment of Inhalant Allergy2iagnosis and Treatment of Inhalant Allergy

,istory and 4hysical E?amination

easonal pollens 4erennial dust* mold* danders

Education* Enironmental &ontrol*4harmacotherapy

Allergy Testing B &onsider screen* then if positie* full +attery of tests

Immunotherapy

If 3ailure


39/77


Air 3iltrationB 4ersonal* Room* ,ouse* &arAir 3iltrationB 4ersonal* Room* ,ouse* &ar

Air 3ilters* inAir 3ilters* in&onsumer&onsumerReports ofReports of1>"--"1>"--"


40/77


Indoor Enironmental Allergen &ontrolBIndoor Enironmental Allergen &ontrolB

E?ample for Allergic (E?trinsic) AsthmaE?ample for Allergic (E?trinsic) Asthma

;-!=-# with asthma hae IgE sensitiities* commonly mite*;-!=-# with asthma hae IgE sensitiities* commonly mite*

coc8roach* cat 9>or Alternaria speciescoc8roach* cat 9>or Alternaria species

Indoor allergen reduction decreases seerity of asthmaBIndoor allergen reduction decreases seerity of asthmaB

! %ite allergen B mite impermea+le mattress 9 pillow%ite allergen B mite impermea+le mattress 9 pillow

coersL wash comforters* +edding* etc at G1.-3L mitecoersL wash comforters* +edding* etc at G1.-3L mite8illing powders (acaricides) on rugs* upholstered8illing powders (acaricides) on rugs* upholstered

furniture* drapesL house humidity < 0-#furniture* drapesL house humidity < 0-#

! &oc8roach allergen B e?termination* cleaning&oc8roach allergen B e?termination* cleaning

! %old B house humidity < 0-#L clean +athrooms*%old B house humidity < 0-#L clean +athrooms*

8itchens* laundry roomsL ent moist areas8itchens* laundry roomsL ent moist areas! ,igh efficiency air filtration 9 acuum cleaner +ags,igh efficiency air filtration 9 acuum cleaner +ags


41/77


Treatment &onsiderations inTreatment &onsiderations in

Allergic RhinitisAllergic Rhinitis

4harmacotherapy 3actors B4harmacotherapy 3actors B! EffectienessEffectieness

! ide effect profileide effect profile

! 2osing schedule2osing schedule

! Afforda+ilityAfforda+ility

Immunotherapy 3actors (Allergy shots) BImmunotherapy 3actors (Allergy shots) B! Effectie in -!=-# with allergic rhinitis* must +e continuedEffectie in -!=-# with allergic rhinitis* must +e continued

for .!0 years in most (seems to reuire such for sustaina+lefor .!0 years in most (seems to reuire such for sustaina+le

leels of +loc8ing anti+odies 9 the li8eL some reuireleels of +loc8ing anti+odies 9 the li8eL some reuirelifelong therapy)lifelong therapy)


42/77


Treatment of Allergic RhinitisTreatment of Allergic Rhinitis

Ty!e o/ Dr"%Ty!e o/ Dr"%AntihistaminesAntihistamines

Intranasal teroidsIntranasal teroids

&romolyn sodium&romolyn sodium

2econgestants2econgestants

7eu8otrienes7eu8otrienes

ImmunotherapyImmunotherapy

IgE specific agentsIgE specific agents

A.#ionA.#ion'loc8 histamine'loc8 histamine

7ocal anti!inflammatory7ocal anti!inflammatory

ta+ilies mast cellsta+ilies mast cells

DasoconstrictionDasoconstriction

'loc8 cyto8ine action'loc8 cyto8ine action

&ompeting anti+odies* etc/&ompeting anti+odies* etc/

'ind IgE* +loc8 receptor'ind IgE* +loc8 receptor

sites* etc/sites* etc/


43/77


Effects of Darious 4harmacotherapiesEffects of Darious 4harmacotherapies:herapy:herapy 0nee1ing0nee1ing "hinorrhea"hinorrhea

NasalNasalostructionostruction

Nasal itchNasal itch$ye$ye

symptomssymptoms

HH%%/antihistamines/antihistaminesOralOral ; ;; ; ; ;; ; ;; ; ; ;; ; ; ; ;; ;

IntranasalIntranasal ; ;; ; ; ;; ; ;; ; ;; ;

IntraocularIntraocular ; ; ;; ; ;

2orticosteroids2orticosteroids

IntranasalIntranasal ; ; ;; ; ; ; ; ;; ; ; ; ; ;; ; ; ; ;; ; ; ;; ;

2romolyn sodium2romolyn sodium

IntranasalIntranasal ;; ;; ;; ;;

IntraocularIntraocular ; ;; ;

DecongestantsDecongestants

IntranasalIntranasal ; ; ; ;; ; ; ;

OralOral ;;

AnticholinergicsAnticholinergics ; ;; ;

Antileu


44/77


%ild%ildintermittentintermittent

%ild%ildpersistentpersistent%oderate!%oderate!

seereseereintermittentintermittent

%oderate!%oderate!seereseere

persistentpersistent

4atient education andallergen and irritant aoidance

Immunotherapy* if otherImmunotherapy* if other therapiestherapiesfailfail

4atient education and allergen aoidance

Intranasal decongestant (


45/77


$er the &ounter ($T&) Allergy %edicationsBAccessi+le* at modest cost in most cases

%ost current $T& antihistamines* may causedrowsiness* dry mouth* +lurry ision*

constipation 9 urinary retention

$ral decongestants may cause agitation 9sleeplessness* or eleate +lood pressure

Topical decongestants can lead to re+oundcongestion or rhinitis medicamentosa

&romolyn reuires freuent dosing prior to 9during e?posure

Traditional 2rug TherapiesTraditional 2rug Therapies


46/77


Topical 9 $ral 2econgestantsTopical 9 $ral 2econgestants(action per alpha adrenergic receptors* do not reliee(action per alpha adrenergic receptors* do not reliee

rhinitis* pruritis* sneeing)rhinitis* pruritis* sneeing)

Topical 2econgestantsTopical 2econgestants(neosynephrine* o?ymetaoline)(neosynephrine* o?ymetaoline)hrin8 inflamed 9 swollen mucosa through localhrin8 inflamed 9 swollen mucosa through local

asoconstrictionasoconstriction

se no longer than ! days to aoid re+oundse no longer than ! days to aoid re+ound$ral 2econgestants$ral 2econgestants(pseudoephedrine)(pseudoephedrine)

Reduce nasal +lood flow (hence* edema 9Reduce nasal +lood flow (hence* edema 9

hyperemia) 9 may improe sinus ostial patencyhyperemia) 9 may improe sinus ostial patency

%ay +e used indefinitely%ay +e used indefinitely(watch '4* sleep* an?iety* 9 use(watch '4* sleep* an?iety* 9 usewith caution if dia+etes* glaucoma* prostatic hypertrophy*with caution if dia+etes* glaucoma* prostatic hypertrophy*

AD2* etc/)AD2* etc/)


47/77


Reliees rhinitis* e?cess mucous production* as wellas most ocular 9 non!nasal manifestions* +ut notn$s$ .on%es#ionwith short term therapy

%inimal to no sedation (mental alertness 9coordination usually intact)

%ucosal drying aria+ly present (much less amongthan older antihistamines)L consider topicalantihistamine alternatie in those with seere asthmaor +ronchitis

&ostlier than $T& > older generation antihistamines(though most sedate to arying degrees)

4rescription Antihistamines4rescription Antihistamines


48/77


Topically effectie in relieing sneeing* nasalpruritis* rhinorrhea 9 reactie mucosal edema

%inimal systemic a+sorption for most(in youngerchildren* use drugs least a+sor+ed 9 effectie with oncedaily dosing* particularly if also on steroids for asthma)

Effectieness depends on regular use 9 adeuatenasal airway for delieryL reuires at least day or

two +efore clinical onset of action(may need oraldecongestant for first wee8 to aid penetration)Lcan irritate

nasal mucosaL modest effect on ocular symptoms

Topical Nasal teroidsTopical Nasal teroids


49/77


7eu8otriene uppressors7eu8otriene uppressors

7eu8otriene synthesis inhi+itors or receptor7eu8otriene synthesis inhi+itors or receptorantagonists commonly used for asthma (afterantagonists commonly used for asthma (after

therapies with inhaled steroids 9 '!agonists fail)therapies with inhaled steroids 9 '!agonists fail)

&onsider in patients with persisting symptoms&onsider in patients with persisting symptoms

despite topical steroids 9>or antihistamines*despite topical steroids 9>or antihistamines*especially in asthmatics or those with AA triadespecially in asthmatics or those with AA triad

%ay +e useful (aria+le effect) on polyps or%ay +e useful (aria+le effect) on polyps or

hyperplastic nasal > sinus mucosahyperplastic nasal > sinus mucosa

3ew side effects* safe in children G "y>o3ew side effects* safe in children G "y>o


50/77


%ast &ell ta+iliersB%ast &ell ta+iliersBcromolyn ornedocromil in nasal* ophthalmic or inhaledpreparations

AnticholinergicsBAnticholinergicsB topical atropine oripratropium

IgE 'loc8ers > 'indersBIgE 'loc8ers > 'indersBomaliuma+ (as aperiodic shot)* many in pipeline for releasein ne?t few years

alineBalineBsaline sprays* pumped irrigations

$ther Therapies for Inhalant Allergies$ther Therapies for Inhalant Allergies


51/77


Types of 8in TestingTypes of 8in Testing

4atch test4atch test(derm use only)(derm use only)

cratch Testcratch Test

(poor(poorreproduci+ility)reproduci+ility)

Pri.k Tes#Pri.k Tes#

! single pric8 testsingle pric8 test! multi!test deicesmulti!test deices

! Intradermal TestsIntradermal Tests!single intradermal!s8in endpoint

titration (serialdilutions* multipletests to uantitatesensitiity)


52/77


Identify antigens in patient:s enironment(regional* wor8 9 home)

uccessful immunotherapy* 9enironmental modification* depends uponaccurate determination of all (or at least the

maCority) of clinically significant allergens

election of Antigens for 8in orelection of Antigens for 8in or

7a+oratory Testing7a+oratory Testing


53/77


Pri.k Tes#in%Pri.k Tes#in%

trength of antigen predeterminedtrength of antigen predetermined! usually 1B1- or 1B"- antigen weight to olume of liuidusually 1B1- or 1B"- antigen weight to olume of liuid

Antigen placed on s8in (+ac8 or arm) prior toAntigen placed on s8in (+ac8 or arm) prior topric8* s8in is tented up with sharp instrument 9pric8* s8in is tented up with sharp instrument 9then pric8edthen pric8ed

Reactions are determined after "- minutesReactions are determined after "- minutes 5rading system 1Q to Q* measuring +oth wheal5rading system 1Q to Q* measuring +oth wheal

and erythema flare responsesand erythema flare responses

2esigned to detect maCor sensitiities* without2esigned to detect maCor sensitiities* without

uantitation as to degreeL can miss low gradeuantitation as to degreeL can miss low gradesensitiities such as moldssensitiities such as molds


54/77


ingle 4ric8 $ptions

%ulti 4ric8 (arious deices* all of which accomplishsimultaneous punctures with different antigens)

8in 4ric8 Techniues8in 4ric8 Techniues


55/77


Intradermal Testing B ingle AntigenIntradermal Testing B ingle Antigen

&oncentration Tests&oncentration Tests

trength of antigen predeterminedtrength of antigen predetermined! usually -/-1 J -/-cc of 1B0-- to 1B1--- antigen weight tousually -/-1 J -/-cc of 1B0-- to 1B1--- antigen weight to

olume inCected su+cutaneouslyolume inCected su+cutaneously

Reaction read after 1-!"- minutesReaction read after 1-!"- minutes

5rading system 1Q to Q * measure +oth wheal sie5rading system 1Q to Q * measure +oth wheal sie

9 erythema flare responses9 erythema flare responses

2etects maCor sensitiities +ut without uantitatie2etects maCor sensitiities +ut without uantitatie

informationL can detect most low gradeinformationL can detect most low grade

sensitiities if 1B0-- antigen solution utiliedsensitiities if 1B0-- antigen solution utilied


56/77


8in Endpoint (2ilutional) Titration8in Endpoint (2ilutional) Titration

or ETor ET Intradermal inCection of -/-1!-/-" cc of seriallyIntradermal inCection of -/-1!-/-" cc of serially

diluted antigen (usually 1B0* starting with the antigendiluted antigen (usually 1B0* starting with the antigen

concentrate) to produce a mm whealconcentrate) to produce a mm wheal

Reaction read per wheal growth +y 1-!10 minutesReaction read per wheal growth +y 1-!10 minutes If no reaction is detected* progressiely moreIf no reaction is detected* progressiely more

concentrated antigen solutions are inCected until aconcentrated antigen solutions are inCected until a

"mm or more growth in wheal sie occurs or the"mm or more growth in wheal sie occurs or the

highest concentration of antigen (usually 1B1--highest concentration of antigen (usually 1B1--

weight per olume) dilution is reached* signaling noweight per olume) dilution is reached* signaling no

significant sensitiity to the antigensignificant sensitiity to the antigen


57/77


-/-1!/-"cc intradermal testproduces mm wheal

preads to 0mm +y diffusion

If it further enlarges G"mm after1-!10 minutes* test is li8elypositie(i/e/* patient sensitie to the antigen*+ut such must +e confirmed +y yet another "mmwheal growth when the ne?t stronger antigen isinCected)

"

#

$

ET 2iagramET 2iagram

erial Endpoint (2ilutional) 8in Testingerial Endpoint (2ilutional) 8in Testing


58/77


erial Endpoint (2ilutional) 8in Testingerial Endpoint (2ilutional) 8in Testingfor Identification and uantification offor Identification and uantification of

Inhalant ensitiitiesInhalant ensitiities


59/77


Adantages'Dery safe* and can detect low leels of patientsensitiity to an antigen3ew false posities or false negaties

'oth uantitatie and ualitatie (i/e/* identifiesnot only patient sensitiities* +ut magnitude ofthose sensitiities)afe guide to starting therapy

8in Endpoint (2ilutional) Titration8in Endpoint (2ilutional) Titration

- -1 l fAntigen 2oseAntigen 2ose


60/77


-/-1 ml ofarious antigendilutions

deliered +y ET

K; M -/-. g

K0 M -/1; gK M -/=- g

K. M /- g

K" M "- g

K1 M 1-- g

4ric8 1B1- w>M /.- g

-/-"mlingle I2 1B1--- w>M "- g

-/-"mlingle I2 1B0-- w>M- g

Antigen 2oseAntigen 2ose

&omparisons among&omparisons among

8in Testing8in TestingTechniuesTechniues


61/77


Allergen coupled to a solid phase B 4aper dis8(RAT)* &ellulose sponge (Immuno&A4* etc/)

Add patient:s serum

Antigen!Anti+ody comple? formed Anti! IgE added

Anti!IgE Anti+ody!Allergen comple? formed

&omputeried reading of different tags(radioactie* fluorescence* colorimetric*enymatic)

In Ditro Testing 4rocedureIn Ditro Testing 4rocedure

andwich Assay Techniueandwich Assay Techniue


62/77


In Ditro %ethodologyIn Ditro %ethodology

Courtesy cientific American

Allergen coupled to a solid phase B paper dis8 or cellulose spongeAdd patient:s serum* 9IgE Anti+ody!Allergen comple?esformed

(9 possi+ly some Ig5 Anti+ody!Allergen comple?es)Add Anti!IgE* 9Anti!IgE Anti+ody!IgE Anti+ody!Allergen comple?esformed&omputeried reading of different tags (radioactie* fluorescence*colorimetric* enymatic)

% difi d I Di i


63/77


(uantifies patient sensitiity per scale that reflectsamount of specific IgE andcorrelates with ET resultsL

RAT!specific scale shown )

&lass - "0- ! 0-- (Not sensitie)

&lass 1>- 0-1 ! 0- (%arginally sensitie)

&lass 1 01 ! 1;-- (7ow sensitiity)

&lass " 1;-1 ! .;--

&lass . .;-1 ! =---

&lass =--1 ! 1=---

&lass 0 1=--1 ! ---- (Dery sensitie)

%odified In Ditro coring%odified In Ditro coring


64/77


2omparison of2omparison of

0coring0coring0ystems0ystems


65/77


Relatie AdantagesBRelatie AdantagesB

In Dio s/ In Ditro TestingIn Dio s/ In Ditro Testing

In Ditro (immunoassay)In Ditro (immunoassay)

No ris8 of allergic reactionNo ris8 of allergic reaction

Not affected +y drugs orNot affected +y drugs or

s8in conditionss8in conditions4atient conenience4atient conenience

(single enipuncture)(single enipuncture)

Easy to document ualityEasy to document uality

control* reproduci+ilitycontrol* reproduci+ility%ost conenient for allergy%ost conenient for allergy

screenscreen

In Dio (s8in tests)In Dio (s8in tests)

5reater sensitiity (e/g/*5reater sensitiity (e/g/*

molds)molds)

7arger aaila+ility of7arger aaila+ility ofantigensantigens

Immediate test resultsImmediate test results

%oderately less e?pense%oderately less e?pense

No la+oratory certificationNo la+oratory certificationpaperwor8paperwor8


66/77


Testing creens of = ! 1- antigens can precede full +attery

Testing with indiidual antigens rather than antigen mi?es

Treatment 2ecision to treat rests on clinical Cudgement* N$T Cust Q results

EN24$INT* a uantification of patient sensitiity* ia ET or%odified RAT score* indicates safe immunotherapy startingdose

Fhen enough sensitiities necessitate " different treatmentials* high 9 low sensitiities are separated 9 different speedsof dose escalation are possi+le (faster with low sensitiityantigens)

4rinciples &ommon to ET4rinciples &ommon to ET

In Dio 9 In Ditro %ethods of TestingIn Dio 9 In Ditro %ethods of Testing

3ood Allergy3ood Allergy


67/77


3ood Allergy3ood Allergy

(" +asic types B 3i?ed and &yclic)(" +asic types B 3i?ed and &yclic)

%ay cause nasal congestion 9 rhinitis* in%ay cause nasal congestion 9 rhinitis* inaddition to more common food sensitiityaddition to more common food sensitiitymanifestationsB 5I distur+ance* rash*manifestationsB 5I distur+ance* rash*headache* ertigoheadache* ertigo

&onsider ealuation if patient has positie&onsider ealuation if patient has positiehistory for food reactionshistory for food reactions (or colic>ecema(or colic>ecemaas child)*as child)*inhalant allergy wor8up isinhalant allergy wor8up isunimpressie* or therapyunimpressie* or therapy (enironmental(enironmentalmodification* pharmacotherapy*modification* pharmacotherapy*immunotherapy)immunotherapy)fails to +ring e?pected relieffails to +ring e?pected relief


68/77


3ood Reactions3ood Reactions

4realence greatest < . years of age* 9 declines4realence greatest < . years of age* 9 declines

oer ne?t decadeoer ne?t decade

-# of food allergy reactions in children are-# of food allergy reactions in children are

caused +y ; foods B mil8* egg* soy (all of which cancaused +y ; foods B mil8* egg* soy (all of which can

+e outgrown)* 9 wheat* peanut* tree nuts+e outgrown)* 9 wheat* peanut* tree nuts

-# of food allergy reactions in adults are caused-# of food allergy reactions in adults are caused+y foodsB peanut* tree nuts* fish* shellfish+y foodsB peanut* tree nuts* fish* shellfish

&ommon cross reactions +etween inhalants 9&ommon cross reactions +etween inhalants 9

foodsB ragweed 9 melon > +ananaL +irch 9foodsB ragweed 9 melon > +ananaL +irch 9

apple > carrot > potato > haelnut > almondapple > carrot > potato > haelnut > almond


69/77


3i?ed 3ood Allergies3i?ed 3ood Allergies

IgE mediated with immediate clinical reaction toIgE mediated with immediate clinical reaction toingestion* freuentlyingestion* freuently angioedema or anaphyla?isangioedema or anaphyla?is

(most freuently shellfish or peanut)(most freuently shellfish or peanut)

2iagnosis usually made from patient history2iagnosis usually made from patient history

! specific IgE assay will confirm if needed (dospecific IgE assay will confirm if needed (do N$TN$Ts8ins8intest for the food)test for the food)

Treatment is aoidance of offending food*Treatment is aoidance of offending food*

patient should +e instructed in use of selfpatient should +e instructed in use of self

administered* inCecta+le epinephrineadministered* inCecta+le epinephrine


70/77


&yclic 3ood Allergies&yclic 3ood Allergies

%ost common type of food sensitiity* with%ost common type of food sensitiity* withdelayeddelayed onset of symptoms (up to " hours)onset of symptoms (up to " hours)

%ediated +y any of the 5ell 9 &oom+s%ediated +y any of the 5ell 9 &oom+s

reactionsreactions! %ost are immune comple? reactions%ost are immune comple? reactions

2iet and symptom diary identify li8ely offending foods2iet and symptom diary identify li8ely offending foods! day elimination of the particular food* and then a &hallenge day elimination of the particular food* and then a &hallenge

feeding test of that food on 0th dayfeeding test of that food on 0th day

! In itro tests are alternatie in young children (higher freuencyIn itro tests are alternatie in young children (higher freuencyof IgE!mediated food reactions)of IgE!mediated food reactions)

Eli i ti 2i t d &h ll 3 d T tEli i ti 2i t d &h ll 3 d T t


71/77


Elimination 2iet and &hallenge 3ood TestElimination 2iet and &hallenge 3ood Test

Eliminate suspect food* in allproducts* +ased on patient history

4atient improes

Reintroduce suspectfood into diet

ymptoms recur

Eliminate food for !0 days*then &hallenge 3ood Test

4atient unchanged

Ealuate other food(s)*consider other origins tosymptoms

I di ti f I thI di ti f I th


72/77


Indications for ImmunotherapyIndications for Immunotherapy

Aoidance 9 Enironmental %easuresAoidance 9 Enironmental %easuresfail to controlfail to control

symptoms* or are impractical (e/g/* teacher in moldysymptoms* or are impractical (e/g/* teacher in moldyschool +uilding* florist sensitie to plant pollens orschool +uilding* florist sensitie to plant pollens or

eterinarian sensitie to cats)eterinarian sensitie to cats)

4harmacotherapy4harmacotherapyfails to fully control symptoms* orfails to fully control symptoms* or

produces +othersome side!effectsproduces +othersome side!effects %oderate to seere symptoms in " or more seasons* 9%oderate to seere symptoms in " or more seasons* 9

8in or In Ditro tests document IgE mediated8in or In Ditro tests document IgE mediated

sensitiitysensitiity

&ontraindications B&ontraindications B !+loc8er or potential pro+lem with!+loc8er or potential pro+lem withepinephrine* poorly controlled asthma* autoimmune orepinephrine* poorly controlled asthma* autoimmune or

immunodeficiency disease* unrelia+le patientimmunodeficiency disease* unrelia+le patient


73/77


Immunotherapy for Allergic RhinitisImmunotherapy for Allergic Rhinitis

Regular inCections of increasing amounts of AllergenRegular inCections of increasing amounts of Allergenadministered eery 0! days until symptom relieingadministered eery 0! days until symptom relieingdose or ma?imum tolerated dose reached* thendose or ma?imum tolerated dose reached* thenmaintenance dose "! wee8s* +ased on symptomsmaintenance dose "! wee8s* +ased on symptoms

&ontinue maintenance dose until symptoms are&ontinue maintenance dose until symptoms arecontrolled for . !0 years* then can discontinuecontrolled for . !0 years* then can discontinueImmunotherapy in a+out 0#Immunotherapy in a+out 0#

InCections during dose escalation under directInCections during dose escalation under directsuperision of physician trained to managesuperision of physician trained to manage

anaphyla?isanaphyla?is

Immunotherapy 3ailureBImmunotherapy 3ailureB


74/77


Immunotherapy 3ailureBImmunotherapy 3ailureB

&ommon Reasons&ommon Reasons

4atient failure to regularly comply with the4atient failure to regularly comply with theimmunotherapy regimenimmunotherapy regimen

Incorrect antigen dosing 9>or too infreuent shotIncorrect antigen dosing 9>or too infreuent shot

interalsinterals

3ood or chemical sensitiities* or inhalants to3ood or chemical sensitiities* or inhalants towhich patient was not tested or for whichwhich patient was not tested or for which

commercial antigens are unaaila+lecommercial antigens are unaaila+le

Non!allergic rhinitis (asomotor* occupational*Non!allergic rhinitis (asomotor* occupational*

atrophic* medication!induced)atrophic* medication!induced) Rhinosinusitis* Anatomic airway o+structionRhinosinusitis* Anatomic airway o+struction

All i 3 l 4 i itiAllergic 3ungal 4ansinusitis


75/77


Allergic 3ungal 4ansinusitisAllergic 3ungal 4ansinusitis


76/77


ummary B Allergic Rhinitisummary B Allergic Rhinitis

Affects 1!"0# of populationAffects 1!"0# of population ymptoms > related diseasesymptoms > related diseases eryery releant to thereleant to the

otolaryngologists (e/g/* nasal congestion*otolaryngologists (e/g/* nasal congestion*

rhinitis* rhinosinusitis* otitis media*rhinitis* rhinosinusitis* otitis media*

pharyngitis* laryngitis)pharyngitis* laryngitis)

Initial diagnosis +y , 9 4* with s8in or in itroInitial diagnosis +y , 9 4* with s8in or in itro teststests

as neededas needed

Treatments aaila+le B aoidance 9>or enironmentalTreatments aaila+le B aoidance 9>or enironmental

measuresmeasures* p* patient counseling*atient counseling* physical fitness*physical fitness*

pharmacotherapy*pharmacotherapy*eradicate comor+idity*eradicate comor+idity*immunotherapyimmunotherapy

R f


77/77

ReferencesReferences

3ornadley S* &orey S* $sguthorpe S* et alB Allergic3ornadley S* &orey S* $sguthorpe S* et alB AllergicRhinitisB &linical 4ractice 5uidelines/ $tolaryngolRhinitisB &linical 4ractice 5uidelines/ $tolaryngol

,ead Nec8 urg 110B110* 1;,ead Nec8 urg 110B110* 1;(consensus of American(consensus of AmericanAcademy of $tolaryngology ! ,ead and Nec8 urgery 9 AmericanAcademy of $tolaryngology ! ,ead and Nec8 urgery 9 AmericanAcademy of $tolaryngic Allergy)/Academy of $tolaryngic Allergy)/

$sguthorpe S* 2ere+ery S (guest editors)B$sguthorpe S* 2ere+ery S (guest editors)B$tolaryngic Allergy/ $tolaryngol &lin N Am .;()*$tolaryngic Allergy/ $tolaryngol &lin N Am .;()*"--./"--./

Hrouse S* &hadwic8 * 5ordon '* 2ere+ery SBHrouse S* &hadwic8 * 5ordon '* 2ere+ery SBAllergy and ImmunologyB An $tolaryngicAllergy and ImmunologyB An $tolaryngic

Approach/ 7ippincott Filliams 9 Fil8ins/ 4hil/Approach/ 7ippincott Filliams 9 Fil8ins/ 4hil/"--"/"--"/

Date post:	23-Feb-2018
Category:	Documents
Upload:	gladys-hartono
View:	224 times
Download:	0 times

Coass II-Allergy Rhinitis

Documents