ASTHMAASTHMA

Andrej Petrov M.D.Andrej Petrov M.D.Assistant Professor of MedicineAssistant Professor of Medicine

Division of Pulmonary, Allergy and Critical Care Division of Pulmonary, Allergy and Critical Care MedicineMedicine

University of Pittsburgh School of MedicineUniversity of Pittsburgh School of Medicine

LECTURE OUTLINELECTURE OUTLINE

EpidemiologyEpidemiology Immunology and pathogenesisImmunology and pathogenesis Clinical presentationClinical presentation DiagnosisDiagnosis Therapy Therapy

DEFINITIONDEFINITION

Chronic inflammatory disorder of the airwaysChronic inflammatory disorder of the airways

Widespread but variable airflow obstruction that is Widespread but variable airflow obstruction that is often reversible either spontaneously or with often reversible either spontaneously or with treatmenttreatment

Bronchial hyperresponsiveness to a variety of Bronchial hyperresponsiveness to a variety of stimulistimuli

Asthma Facts in the United StatesAsthma Facts in the United States

Annual number of hospitalizations: 478,000Annual number of hospitalizations: 478,000 Annual number of deaths from asthma: 4,657Annual number of deaths from asthma: 4,657 Annual number of work days lost: 14.5 millionAnnual number of work days lost: 14.5 million Annual number of school days lost: 14 millionAnnual number of school days lost: 14 million Estimated direct and indirect medical costs: $16 Estimated direct and indirect medical costs: $16

billionbillion

Morb Mortal Wkly Rep. 2002 March 29; 51:1-13.

Adult Asthma FactsAdult Asthma Facts

14.5 million workdays lost due to asthma, a 2.3 14.5 million workdays lost due to asthma, a 2.3 fold increase from the early 80s to the mid 90sfold increase from the early 80s to the mid 90s

Adults accounted for over 1.3 million ED visits Adults accounted for over 1.3 million ED visits and 288,000 hospitalizations due to asthmaand 288,000 hospitalizations due to asthma

One third of asthma related deaths occur in One third of asthma related deaths occur in patients 35-44 years oldpatients 35-44 years old

Over 50% of asthma related deaths occur in Over 50% of asthma related deaths occur in patients 65 years and olderpatients 65 years and older

Morb Mortal Wkly Rep. 2002 March 29; 51:1-13.

Bach, J.-F. N Engl J Med 2002;347:911-920

Inverse Relation between the Incidence of Prototypical Infectious Diseases (Panel A) and the Incidence of Immune Disorders (Panel B) from 1950 to 2000

Most Patients with Asthma Have Allergic Rhinitis

• Approximately 80% of asthmatics have allergic rhinitis

Adapted from The Workshop Expert Panel. Management of Allergic Rhinitis and its Impact on Asthma (ARIA) Pocket Guide. A Pocket Guide for Physicians and Nurses. 2001; Bousquet J and the ARIA Workshop Group J Allergy Clin Immunol 2001;108(5):S147-S334; Sibbald B, Rink E Thorax 1991;46:895-901; Leynaert B et al Am J Respir Crit Care Med 2000;162:1391-1396.

Asthmaalone

Allergic rhinitisalone

Allergicrhinitis

+ asthma

IgE and Asthma in Adults

Asthma

Serum IgE (IU/mL)

Od

ds

rat

io

N = 2657

0.32 1 3.2 10 32 100 320 1000 3200

11

2.52.5

55

1010

2020

4040

Burrows B, et al. New Engl J Med. 1989;320:271-277.

THE HYGIENE HYPOTHESISTHE HYGIENE HYPOTHESIS

Distribution of Dendritic Cells in the LungsDistribution of Dendritic Cells in the Lungs

ALLERGEN SENSITIZATIONALLERGEN SENSITIZATION

Pathways for the natural generation of regulatory Pathways for the natural generation of regulatory T-cell populationsT-cell populations

IgE-dependent Release of Inflammatory 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

Airway Inflammation in AsthmaAirway Inflammation in Asthma

Acute Fatal Asthma

Impact of Inflammation on Small AirwaysImpact of Inflammation on Small Airways

Normal Chronic Severe Asthma

Airway RemodelingAirway Remodeling

Peter Jefferey, AJRCCM 2001

DENDRITIC CELL WITH AN ALLERGEN

DENDRITIC CELL CAPTURES THE ALLERGEN AND RUNS WITH IT TO THE LYMPH NODE

DENDRITIC CELL RELEASES THE

ALLERGEN

T CELL CAPTURES THE ALLERGEN

CELL RECRUITMENT

MUSCLE CELL HYPERTROPHY

TISSUEDAMAG

E

MORE TISSUE DAMAG

E

SYMPTOMSSYMPTOMS

Recurrent episodes of:Recurrent episodes of:• Shortness of breathShortness of breath

• WheezingWheezing

• Chest tightnessChest tightness

• Cough, particularly at night and early in the Cough, particularly at night and early in the morningmorning

Before 10 Minutes After Allergen Challenge

BronchoconstrictionBronchoconstriction

Mechanisms of Airway Mechanisms of Airway ObstructionObstruction

Smooth MuscleContraction

MucusHypersecretion

Loss of ElasticRecoil

? PeribronchialFibrosis

Airway WallEdema

Vascular dilatation

A Scheme of Immune and Inflammatory Events Associated with the Pathophysiology of Asthma, with Emphasis on Early-versus

Late-Phase, Asthmatic Responses.

JACI 2003; 111, 1

PATTERN OF SYMPTOMSPATTERN OF SYMPTOMS

Perennial, seasonal or bothPerennial, seasonal or both

Continual, episodic or bothContinual, episodic or both

Diurnal variations, especially nocturnal and Diurnal variations, especially nocturnal and on awakening early in the morningon awakening early in the morning

PRECIPITATING AND/OR PRECIPITATING AND/OR AGGRAVATING FACTORSAGGRAVATING FACTORS

Viral respiratory infectionsViral respiratory infections Environmental allergensEnvironmental allergens ExerciseExercise Occupational chemicals or allergensOccupational chemicals or allergens IrritantsIrritants Changes in weatherChanges in weather Endocrine factorsEndocrine factors GERDGERD SinusitisSinusitis

PHYSICAL EXAMPHYSICAL EXAM

Normal physical examNormal physical exam Expiratory wheezing with normal or Expiratory wheezing with normal or

decreased air movementdecreased air movement Accessory respiratory muscle useAccessory respiratory muscle use Ominous sign- no wheezing with decreased Ominous sign- no wheezing with decreased

air movementair movement

EVALUATIONEVALUATION

CLINICAL HISTORYCLINICAL HISTORYSPIROMETRYSPIROMETRYMETHACHOLLINE CHALLENGE METHACHOLLINE CHALLENGE

TESTTESTALLERGY SKIN TESTSALLERGY SKIN TESTS

Spirometry: A Simple, Basic MeasurementSpirometry: A Simple, Basic Measurement

Essential to initial evaluationEssential to initial evaluation Helps assess severity of airflow obstructionHelps assess severity of airflow obstruction Aids in differential diagnosisAids in differential diagnosis

• Obstructive versus restrictive airway diseaseObstructive versus restrictive airway disease

• Reversibility of airflow obstructionReversibility of airflow obstruction Confirms periodic home PEFR measurements Confirms periodic home PEFR measurements

in selected patientsin selected patients

Spirometry in asthmaSpirometry in asthma

Decreased FEV1/FVC ratioDecreased FEV1/FVC ratio Improvement in FEV1>12% with Improvement in FEV1>12% with

bronchodilator or therapy bronchodilator or therapy Normal DLCO Normal DLCO Increased residual volume Increased residual volume Normal spirometryNormal spirometry

FlowFlow

(l/s)(l/s)

Volume (l)Volume (l)

-2-2

00

-4-4

11

33

22

44

55

21 3 4 5

-6-6

Pre-albuterolPost-albuterolPredicted

Spirometry: Flow-Volume Loops in Spirometry: Flow-Volume Loops in AsthmaAsthma

Reasons for Performing Bronchoprovocation Reasons for Performing Bronchoprovocation Challenges in Clinical PracticeChallenges in Clinical Practice

Clarify a clinical diagnosis of asthma when a Clarify a clinical diagnosis of asthma when a reasonable degree of doubt existsreasonable degree of doubt exists

To determine the presence of bronchial To determine the presence of bronchial hyperresponsiveness in patients with chronic hyperresponsiveness in patients with chronic coughcough

To quantify the severity of the airway To quantify the severity of the airway hyperresponsivenesshyperresponsiveness

Caveats on BronchoprovocationCaveats on Bronchoprovocation

A positive methacholine or histamine A positive methacholine or histamine challenge is not equivalent to a diagnosis challenge is not equivalent to a diagnosis of asthmaof asthma

A negative histamine or methacholine A negative histamine or methacholine challenge probably excludes current challenge probably excludes current asthmaasthma

Non-asthmatics can have positive Non-asthmatics can have positive methacholine or histamine challengesmethacholine or histamine challenges

ALLERGIC TRIGGERSALLERGIC TRIGGERS

INHALANT ALLERGENSINHALANT ALLERGENS

Animal allergensAnimal allergensHouse-dust mites House-dust mites Cockroach allergensCockroach allergens Indoor fungi (molds)Indoor fungi (molds)Outdoor allergensOutdoor allergens

ALLERGEN SKIN TESTSALLERGEN SKIN TESTS

Eugene Braunwald, Atlas of Internal Medicine, 2nd edition

EVALUATIONEVALUATION

CBC with differential ( eosinophilia often CBC with differential ( eosinophilia often seen in asthma, ABPA and CS vasculitis)seen in asthma, ABPA and CS vasculitis)

Total igETotal igE Optional specific IgE to allergensOptional specific IgE to allergens CXRCXR CT of the chestCT of the chest ABG in status asthmaticusABG in status asthmaticus

ASTHMA CLASSIFICATION AND ASTHMA CLASSIFICATION AND THERAPYTHERAPY

Classification of Asthma - EPR IIClassification of Asthma - EPR II

Intermittent AsthmaIntermittent Asthma MILDMILD

Persistent AsthmaPersistent Asthma MILDMILD

sx frequency < 1/daysx frequency < 1/day

FEV1>60%FEV1>60% MODERATEMODERATE

sx frequency 1/daysx frequency 1/day

FEV1=40-60%FEV1=40-60% SEVERESEVERE

sx frequency > 1/daysx frequency > 1/day

FEV1<40%FEV1<40%

sx frequency less than 2 times / week sx frequency 2 times / week or more

Goals of Therapy: Asthma ControlGoals of Therapy: Asthma Control

■ ■ Minimal or no chronic symptoms day or nightMinimal or no chronic symptoms day or night

■ ■ Minimal or no exacerbationsMinimal or no exacerbations

■ ■ No limitations on activities; no school/work missedNo limitations on activities; no school/work missed

■ ■ Maintain (near) normal pulmonary functionMaintain (near) normal pulmonary function

■ ■ Minimal use of short-acting inhaled beta2-agonistMinimal use of short-acting inhaled beta2-agonist

■ ■ Minimal or no adverse effects from medicationsMinimal or no adverse effects from medications

Symptom Relievers for AsthmaSymptom Relievers for Asthma

Intermittent AsthmaIntermittent Asthma MILDMILD

PRN PRN -agonist QID-agonist QID

Persistent AsthmaPersistent Asthma MILDMILD

PRN PRN -agonist QID-agonist QID MODMOD

PRN PRN -agonist QID-agonist QID SEVERESEVERE

PRN PRN -agonist QID-agonist QID

Controllers for AsthmaControllers for Asthma

Intermittent AsthmaIntermittent Asthma MILDMILD

NoneNone

Persistent AsthmaPersistent Asthma MILDMILD

Low dose ICS or LT blockerLow dose ICS or LT blocker MODERATEMODERATE

Mod dose ICSMod dose ICS

+ LA Bronchodilator+ LA Bronchodilator

+ LT Blocker+ LT Blocker SEVERESEVERE

High dose ICSHigh dose ICS

+ LA Bronchodilator+ LA Bronchodilator

+ LT Blocker+ LT Blocker

OCSOCS

Omalizumab Characteristics

• Humanized mAb against IgE

• Binds circulating IgE

regardless of specificity

• Forms small, biologically inert Omalizumab:IgE complexes

• Does not activate complement

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

Omalizumab Blocks IgE Binding to Mast Cells

Mast cell

IgE molecule

FcRI receptor

Omalizumab Omalizumab

THE FUTURE ASTHMA THERAPIESTHE FUTURE ASTHMA THERAPIES

"I used to think that I could "I used to think that I could outrun my asthma. I'd just outrun my asthma. I'd just take my quick-relief medicine take my quick-relief medicine when I had trouble breathing, when I had trouble breathing, and everything was cool.and everything was cool.

"My asthma finally tackled me "My asthma finally tackled me during a big game, and I had during a big game, and I had to be carried off the field. And to be carried off the field. And that's when it hit me:that's when it hit me:

I should be playing offense, I should be playing offense, not defensenot defense

So now I follow my doctor's So now I follow my doctor's advice and a daily treatment advice and a daily treatment plan that helps prevent plan that helps prevent symptoms from occurring in symptoms from occurring in the first place.the first place.

"Whether you're running for "Whether you're running for the end zone, or heading for the end zone, or heading for other goals, don't let asthma other goals, don't let asthma get in the way." get in the way."

Thank you!!Thank you!! Comprehensive Comprehensive

Lung Center, Lung Center, UPMCUPMC

Tel: 412-648-Tel: 412-648-61616161