Allergic Asthma: Diagnosis and Treatment Eddie W. Shields, MD Arkansas Allergy and Asthma.
Transcript of 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
Evidence of Causal Role of Evidence of Causal Role of Allergies in Asthma in Allergies in Asthma in
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
Evidence of Causal Role of Evidence of Causal Role of Allergies in Asthma in Allergies in Asthma in
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
ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463.
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
ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463.
Environmental Control Environmental Control Measures:Measures:
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
ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463.
Environmental Control Environmental Control Measures:Measures:
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.
Environmental Control Environmental Control Measures:Measures:
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.
Environmental Control Environmental Control Measures:Measures:
Irritant FactorsIrritant Factors
Avoid irritantsAvoid irritants Tobacco smokeTobacco smoke Perfume, potpourriPerfume, potpourri FormaldehydeFormaldehyde School supplies/environmentSchool supplies/environment
MarkersMarkers Chalk dustChalk dust
ACAAI/AAAAI Joint Task Force. Ann Allergy Asthma Immunol. 1998;81:463.
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