Allergic Asthma: Diagnosis and Treatment Eddie W. Shields, MD Arkansas Allergy and Asthma.

Allergic Asthma:Allergic Asthma:Diagnosis and Diagnosis and

TreatmentTreatment

Eddie W. Shields, MDEddie W. Shields, MDArkansas Allergy and Arkansas Allergy and

AsthmaAsthma

ObjectivesObjectives

Understand the relationship Understand the relationship between asthma and allergic rhinitisbetween asthma and allergic rhinitis

Understand the pathophysiology of Understand the pathophysiology of allergic asthmaallergic asthma

Learn the role of environmental Learn the role of environmental control, pharmacologic therapy, and control, pharmacologic therapy, and allergen immunotherapy in allergic allergen immunotherapy in allergic asthmaasthma

Rhinitis and AsthmaRhinitis and Asthma

High prevalence, high cost illnessesHigh prevalence, high cost illnesses Both illnesses have a major effect of the Both illnesses have a major effect of the

sufferer’s quality of lifesufferer’s quality of life Both illnesses have a strong association Both illnesses have a strong association

with allergywith allergy Both rhinitis and asthma have common Both rhinitis and asthma have common

inflammatory pathwaysinflammatory pathways Improved control of rhinitis leads to Improved control of rhinitis leads to

improve asthma outcomesimprove asthma outcomes

Leading Chronic Leading Chronic Conditions*Conditions*

in Children Aged <18 in Children Aged <18 YearsYears

40

30

20

10

0

Cases per

1000 Children

N=3355

*Patient assessment.Adapted from Newacheck et al. J Pediatr. 1994;124:40.

Hay FeverAsthma OtherRespiratory

Allergies

DigestiveAllergies

CardiacConditions

SkinAllergies

50

OtherNonallergicConditions

60

70

80

Allergic RhinitisAllergic Rhinitis CHRONIC Inflammatory Disease of the Upper CHRONIC Inflammatory Disease of the Upper

Airways Airways 35 million Americans have allergic rhinitis–35 million Americans have allergic rhinitis–

Prevalence of 10-20% of the populationPrevalence of 10-20% of the population Peak prevalence in children and young adultsPeak prevalence in children and young adults 50% of patients have symptoms >4 months per year and 50% of patients have symptoms >4 months per year and

20% >9 months per year20% >9 months per year ProductivityProductivity

28 million days of restricted activity28 million days of restricted activity 2 million lost school days2 million lost school days

Cost of treatmentCost of treatment $3.5 billion total cost associated with allergic rhinitis $3.5 billion total cost associated with allergic rhinitis

treatmenttreatment

AsthmaAsthma

CHRONIC Inflammatory Disease of CHRONIC Inflammatory Disease of the Lower Airwaysthe Lower Airways

Affects about 3-4% of the Affects about 3-4% of the populations; 7% of childrenpopulations; 7% of children

Most common non-traumatic Most common non-traumatic admission to children’s hospitals in admission to children’s hospitals in the U.S.the U.S. Greater 200,000 hospitalizations per Greater 200,000 hospitalizations per

year in U.S.year in U.S.

Evidence of Causal Role of Evidence of Causal Role of Allergies in Asthma in Allergies in Asthma in

ChildrenChildren Sensitization to indoor allergens and Sensitization to indoor allergens and

outdoor fungi increases the risk for outdoor fungi increases the risk for asthmaasthma The larger the size of the skin test The larger the size of the skin test

reaction to house dust mite, the more reaction to house dust mite, the more sensitive the patient is to methacholine, sensitive the patient is to methacholine, a measure of bronchial hyper-reactivity.a measure of bronchial hyper-reactivity.

JK Peat, et al. N.Z. Med J 1994;24:270


ChildrenChildren Severity of asthma is related to the Severity of asthma is related to the

level of allergen exposurelevel of allergen exposure 18 episodes of sudden onset, 18 episodes of sudden onset,

respiratory arrest in 11 patients, ages respiratory arrest in 11 patients, ages 11-25 years11-25 years

All occurred in summer and early fallAll occurred in summer and early fall 10/11 skin test positive for Alternaria10/11 skin test positive for Alternaria Peak Alternaria season is June to Peak Alternaria season is June to

NovemberNovemberO’Hollaren, et al. NEJM 1991; 324:359-63


ChildrenChildren Reduction of allergen exposure Reduction of allergen exposure

improves asthma symptoms and improves asthma symptoms and pulmonary function and reduces pulmonary function and reduces bronchial hyper-responsiveness.bronchial hyper-responsiveness.

Rhinitis in Asthmatic Rhinitis in Asthmatic ChildrenChildren

Approximately 80% of children Approximately 80% of children presenting with asthma have rhinitis presenting with asthma have rhinitis (1)(1)

Children with a history of allergic Children with a history of allergic rhinitis are more likely to suffer from rhinitis are more likely to suffer from exercise-induced bronchospasm (2)exercise-induced bronchospasm (2)

(1) Mercer et al. S Afr Med J 1991(2) Bradsford et al. Int Arch Allergy Appl Immunol 1991

Allergic Rhinitis as a Allergic Rhinitis as a Risk Factor for Risk Factor for

Developing Asthma, a 23 Developing Asthma, a 23 yr Follow-upyr Follow-up

Diagnosis as freshman

Total at risk

New asthma

% p value

AR 152 17 10.5

<0.002

Non-AR 528 19 3.6

Total 690 36 5.2

Diagnosis as freshman

Total at risk

New asthma

% p value

AR 152 17 10.5

<0.002

Non-AR 528 19 3.6

Total 690 36 5.2

Settipane et al. Allergy Proc 1994

Hypotheses for Links of Hypotheses for Links of Rhinitis and AsthmaRhinitis and Asthma

Both associated with allergyBoth associated with allergy Common ciliated epitheliumCommon ciliated epithelium Similar allergens are associated with Similar allergens are associated with

both conditionsboth conditions Both have a familial link with atopyBoth have a familial link with atopy Possible pathophysiological Possible pathophysiological

mechanism-sino-bronchial reflexmechanism-sino-bronchial reflex

Pathophysiology Pathophysiology of of

Allergic Rhinitis Allergic Rhinitis and Asthmaand Asthma

Phase 1 – SensitizationPhase 1 – Sensitization

AllergenAntigen-

presentingcell

B cell

Processedallergen

CD4T cell

Plasma cell IgE antibodies

Adapted from Naclerio. N Engl J Med. 1991;325:860-869.

TH0

TH1

TH2

Interferon Interleukin 2

Cell-mediatedImmunity

Interleukin 2Interleukin 5

Interleukin 13

Allergic DiseaseHumoral Immunity

Intracellular PathogensInterleukin 12

AllergensInterleukin 4

JAMA. 1997;278:1845.

Phase 2 – Clinical Phase 2 – Clinical DiseaseDisease

Adapted from Naclerio. N Engl J Med. 1991;325:860-869

EarlyPhase

LatePhase

Allergen

IgE antibodies Resolution

Complications

CellularInfiltration

Glands

NervesBloodvessels

SneezingItching

RhinorrheaCongestion

Mediatorrelease Eosinophils

BasophilsMonocytesLymphocytes

Mastcell

IrreversibleDisease?

Priming

Hyper-responsiveness

Late-phasereaction

Overview of the Allergic Overview of the Allergic Inflammatory Cascade in Patients Inflammatory Cascade in Patients

with IgE-mediated Asthmawith IgE-mediated Asthma

Release of IgE

Plasma cell

B lymphocyte

-switch

Allergic Exacerbation

AllergicInflammation:

eosinophils and lymphocytes

Allergens

Mast cellsBasophils

Allergic mediators

IgE-dependent Release of IgE-dependent Release of Inflammatory MediatorsInflammatory Mediators

IgEAllergens

FcRI

Over MinutesLipid mediators: ProstaglandinsLeukotrienes

WheezingBronchoconstriction

Over HoursCytokine production:Specifically IL-4, IL-13

Mucus productionEosinophil recruitment

Immediate ReleaseGranule contents:Histamine, TNF-, Proteases, Heparin

Sneezing Nasal congestionItchy, runny noseWatery eyes

Management of Allergic Management of Allergic Rhinitis and AsthmaRhinitis and Asthma

Education Education Environmental ControlEnvironmental Control Proper Pharmacologic TreatmentProper Pharmacologic Treatment Allergen Vaccination Allergen Vaccination

(Immunotherapy)(Immunotherapy)

Asthma EducationAsthma Education Define asthma and explain treatment Define asthma and explain treatment

optionsoptions Need to adhere to treatment planNeed to adhere to treatment plan Discuss patient’s fear about asthma and Discuss patient’s fear about asthma and

its treatmentits treatment Conduct regularly scheduled follow-up Conduct regularly scheduled follow-up

office visitsoffice visits Provide written asthma action planProvide written asthma action plan

Treatment schedule, peak flow zones, and Treatment schedule, peak flow zones, and emergency numbersemergency numbers

Environmental ControlEnvironmental Control

Major triggers of Allergic Rhinitis Major triggers of Allergic Rhinitis and Asthmaand Asthma PollensPollens MoldsMolds House dust mitesHouse dust mites AnimalsAnimals Insect aeroallergens (eg, moths)Insect aeroallergens (eg, moths)

ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463.

HackberryHackberry

OakOak

WillowWillow

GrassGrass

Environmental Control Environmental Control Measures: PollenMeasures: Pollen

Close windows, doorsClose windows, doors Avoid window/attic fansAvoid window/attic fans A/C on recirculateA/C on recirculate

Reduce outdoor exposure as practicality Reduce outdoor exposure as practicality allows:allows: When pollen counts are highWhen pollen counts are high

Highest in early AMHighest in early AM On sunny, windy days with low humidityOn sunny, windy days with low humidity Shower or bathe following exposureShower or bathe following exposure

ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463-518.

MoldMold

Environmental Control Environmental Control Measures: MoldsMeasures: Molds

Remain in closed environment as Remain in closed environment as practicality allowspracticality allows A/C units, though helpful, can harbor moldA/C units, though helpful, can harbor mold

Avoid lawn mowing, raking leaves, etcAvoid lawn mowing, raking leaves, etc Face masks can be of some valueFace masks can be of some value

Avoid/remedy dampnessAvoid/remedy dampness DehumidifierDehumidifier

Minimize humidifier useMinimize humidifier use If used, keep very cleanIf used, keep very clean


Environmental Control Environmental Control Measures:Measures:

House Dust MitesHouse Dust Mites

Vigorous methods Vigorous methods necessarynecessary Ordinary Ordinary

vacuuming/dusting vacuuming/dusting have little effecthave little effect

Simple furnishings Simple furnishings without without carpetingcarpeting Especially bedroom, Especially bedroom,

family family room, etcroom, etc

Plastic, leather, wood Plastic, leather, wood arearebestbest



House Dust MitesHouse Dust Mites

Wash bedclothes at 130Wash bedclothes at 130ooFF Lower temperatures do not kill mitesLower temperatures do not kill mites

Allergen-proof pillows, mattresses, box Allergen-proof pillows, mattresses, box springssprings Avoid/cover quilts and comfortersAvoid/cover quilts and comforters

Cleaning of duct work has no Cleaning of duct work has no demonstrated value demonstrated value in removing dust mitesin removing dust mites



Animal AllergensAnimal Allergens

All furry/feathered animalsAll furry/feathered animals Cat/dog reactivity found in 25% to 33% of Cat/dog reactivity found in 25% to 33% of

patients patients with ARwith AR

Avoidance most effectiveAvoidance most effective Remove pets from home, if possibleRemove pets from home, if possible Confine animal(s) to noncarpeted room (not Confine animal(s) to noncarpeted room (not

bedroom)bedroom) HEPA filter in animal room may reduce allergens HEPA filter in animal room may reduce allergens

in rest of homein rest of home Eliminate/move litter boxesEliminate/move litter boxesACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol.

1998;81:463.


Insect AllergensInsect Allergens Debris of cockroaches, crickets, flies, Debris of cockroaches, crickets, flies,

moths, etcmoths, etc Careful sanitationCareful sanitation

Eliminate open or standing food, dirty dishesEliminate open or standing food, dirty dishes Store garbage in tightly closed containersStore garbage in tightly closed containers

Roach trapsRoach traps Consider professional Consider professional

extermination/relocation if extermination/relocation if infestation is heavyinfestation is heavyACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463.


Irritant FactorsIrritant Factors

Avoid irritantsAvoid irritants Tobacco smokeTobacco smoke Perfume, potpourriPerfume, potpourri FormaldehydeFormaldehyde School supplies/environmentSchool supplies/environment

MarkersMarkers Chalk dustChalk dust


Medical Management of Medical Management of AsthmaAsthma

Goals of Asthma Goals of Asthma ManagementManagement

Goals of Asthma Goals of Asthma ManagementManagement

Primary goalPrimary goal The asthmatic patient should be to do ALL The asthmatic patient should be to do ALL

normal activitiesnormal activities Other goalsOther goals

Maintain normal or near normal pulmonary Maintain normal or near normal pulmonary functionfunction

Prevent chronic symptoms and recurrent Prevent chronic symptoms and recurrent exacerbationsexacerbations

No emergency department visits or No emergency department visits or hospitalizationshospitalizations

Prevent irreversible lung diseasePrevent irreversible lung disease Minimize need for rescue medicationsMinimize need for rescue medications Avoid adverse reactions from medicationsAvoid adverse reactions from medications

Changes In Airway Changes In Airway Morphology in AsthmaMorphology in Asthma

Smooth musclecontraction

Edema

Vasodilation

Hypertrophy ofmucous gland,hypersecretionof mucus

Infiltration ofinflammatorycells

Loss of epithelium;Thickening & fibrosisof basement and sub-basementmembrane

Omalizumab Omalizumab CharacteristicsCharacteristics

Humanized mAb against Humanized mAb against IgEIgE

Binds circulating IgE Binds circulating IgE

regardless of specificityregardless of specificity Forms small, biologically Forms small, biologically

inert Omalizumab:IgE inert Omalizumab:IgE complexescomplexes

Does not activate Does not activate complementcomplement

Adapted with permission from Boushey H. J Allergy Clin Immunol. 2001;108:S77-S83.

Murine CDRs*(< 5% of molecule)

IgG1 kappa Human

framework(> 95% of molecule)

*CDR = complementarity-determining region

IgE Binds to Mast Cells IgE Binds to Mast Cells at the High Affinity at the High Affinity Receptor (FcReceptor (FcRI) RI)

IgE molecule bound to mast cell

Mast cell

FcRI receptor

IgE molecule

FcRI binding site

Omalizumab Blocks IgE Omalizumab Blocks IgE

Binding to Mast CellsBinding to Mast Cells

Mast cell

IgE molecule

FcRI receptor

Omalizumab Omalizumab

The administration of low then The administration of low then sequentially increasing doses of sequentially increasing doses of allergens in patients with IgE allergens in patients with IgE mediated diseases:mediated diseases:

Allergic RhinoconjunctivitisAllergic Rhinoconjunctivitis Allergic AsthmaAllergic Asthma Insect Sting AnaphylaxisInsect Sting Anaphylaxis

The administration of low then The administration of low then sequentially increasing doses of sequentially increasing doses of allergens in patients with IgE allergens in patients with IgE mediated diseases:mediated diseases:

Allergic RhinoconjunctivitisAllergic Rhinoconjunctivitis Allergic AsthmaAllergic Asthma Insect Sting AnaphylaxisInsect Sting Anaphylaxis

Allergen Immunotherapy

ImmunotherapyImmunotherapy Allergen skin testing should be Allergen skin testing should be

considered in patients with allergic considered in patients with allergic rhinitis and asthma with persistent rhinitis and asthma with persistent symptoms to determine possible allergen symptoms to determine possible allergen triggerstriggers

Highly effective; disease modifyingHighly effective; disease modifying CandidatesCandidates

Moderate to severe symptomsModerate to severe symptoms Lack of improvement with other modalitiesLack of improvement with other modalities Presence of comorbid conditionsPresence of comorbid conditions Evidence of specific IgE sensitization based on Evidence of specific IgE sensitization based on

testingtesting Risk of anaphylaxisRisk of anaphylaxis Oral drops and low dose (provocation-Oral drops and low dose (provocation-

neutralization technique) immunotherapy neutralization technique) immunotherapy have not been proven effective in clinical have not been proven effective in clinical studiesstudies

Impact of Impact of Immunotherapy on Immunotherapy on

Allergic Rhinitis CostsAllergic Rhinitis Costs

0

500

1000

1500

2000

2500

3000

3500

4000

Allergic Rhinitis

RxRx + Imm 3 yrsRx + Imm 10 yrs

DollarsOver 10Years

Sullivan in Current Views in… 1998

How early should we How early should we consider Immunotherapy?consider Immunotherapy?

Prevention of Asthma OnsetPrevention of Asthma Onset Preventive Allergy Treatment study in Preventive Allergy Treatment study in

Northern Europe:Northern Europe: Development of new allergies is Development of new allergies is

decreased and the progression to decreased and the progression to asthma is decreasedasthma is decreased 50% reduction in asthma in children with 50% reduction in asthma in children with

moderate to severe allergic rhinitis who moderate to severe allergic rhinitis who received IT compared to those without ITreceived IT compared to those without IT

Moller C. et al, JACI 2002;109:251-256

How early should we How early should we consider Immunotherapy?consider Immunotherapy? Prevention of New Sensitizations Prevention of New Sensitizations

in childrenin children 22 children with HDM allergy only22 children with HDM allergy only IT for 3 years with HDM extractIT for 3 years with HDM extract

PTs New SensitivitiesPTs New Sensitivities

None cat dog Alt GrassNone cat dog Alt Grass

IT 22 10 6 4 2 1IT 22 10 6 4 2 1

Con 22 0 12 8 6 6Con 22 0 12 8 6 6

p<.001p<.001A Des Roches, et al. JACI 1997; 99:450

How early should we How early should we consider Immunotherapy?consider Immunotherapy?

Prevention of New SensitizationsPrevention of New Sensitizations GB Pajno, et al. Clin Exp Allergy GB Pajno, et al. Clin Exp Allergy

2001;31:1392-72001;31:1392-7 F Purello-D’Ambrosio, et al. Clin Exp F Purello-D’Ambrosio, et al. Clin Exp

Allergy 2001;31:1295-1302Allergy 2001;31:1295-1302

Key Advances in Key Advances in ImmunotherapyImmunotherapy

IT in children with only AR decreases IT in children with only AR decreases asthma asthma

Decreases bronchial hyper-responsiveness Decreases bronchial hyper-responsiveness to methacholineto methacholine

Reduces risk of developing new allergiesReduces risk of developing new allergies Routine series is for 3-5 yearsRoutine series is for 3-5 years Gives long lasting relief of symptomsGives long lasting relief of symptoms High-dose sublingual IT appears to be High-dose sublingual IT appears to be

safe but less effective than injections and safe but less effective than injections and cost savings aren’t clear because of cost savings aren’t clear because of amount of extract requiredamount of extract required

Allergy Prevention Allergy Prevention StrategiesStrategies

Promote breast feedingPromote breast feeding Discourage early introduction of Discourage early introduction of

solid and “at risk” food (milk, eggs, solid and “at risk” food (milk, eggs, peanuts, seafood, ? meats)peanuts, seafood, ? meats)

Reduce dust mite levels in homesReduce dust mite levels in homes Avoid exposure to animal danderAvoid exposure to animal dander Screen for allergy at all routine Screen for allergy at all routine

examsexams Encourage awareness of allergen Encourage awareness of allergen

control measures at work, school, control measures at work, school, and daycareand daycare

Consultation with Consultation with SpecialistSpecialist

Identification of allergic / non-allergic Identification of allergic / non-allergic triggerstriggers

Education in allergen avoidance and controlEducation in allergen avoidance and control If allergen immunotherapy is a considerationIf allergen immunotherapy is a consideration If patient’s quality of life is significantly If patient’s quality of life is significantly

affectedaffected Co-morbidities: asthma, recurrent sinusitis / Co-morbidities: asthma, recurrent sinusitis /

OM, nasal polypsOM, nasal polyps Duration of rhinitis > 3 months and / or Duration of rhinitis > 3 months and / or

requires systemic corticosteroids to managerequires systemic corticosteroids to manage Poor control – persistent symptomsPoor control – persistent symptoms

Allergic Asthma: Diagnosis and Treatment Eddie W. Shields, MD Arkansas Allergy and Asthma.

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Transcript of Allergic Asthma: Diagnosis and Treatment Eddie W. Shields, MD Arkansas Allergy and Asthma.