AsthmaAsthmaKim Otsuka, MDKim Otsuka, MD

Pediatric Pulmonary FellowPediatric Pulmonary Fellow

September 21, 2004September 21, 2004

UoA PPC 2004 Workshop UoA PPC 2004 Workshop LecturesLectures

ObjectivesObjectives

Overview of asthmaOverview of asthma Review NHLBI guidelines for asthma Review NHLBI guidelines for asthma

treatment treatment Review other management strategies Review other management strategies

for asthmafor asthma

What is AsthmaWhat is Asthma Disease of chronic Disease of chronic

airway inflammationairway inflammation Characterized byCharacterized by

– Airway inflammationAirway inflammation– Airflow obstructionAirflow obstruction– Airway Airway

hyperresponsivenesshyperresponsiveness

http://health.allrefer.com/health/asthma-normal-versus-asthmatic-bronchiole.html

Cookson W. Nature 1999; 402S: B5-11

PathophysiologyPathophysiology Caused byCaused by

– Inflammation and Inflammation and edemaedema

– Bronchial smooth Bronchial smooth muscle spasm and muscle spasm and hypertrophyhypertrophy

– Mucous plugging Mucous plugging

Jenkins, HA, et al. Chest 2003; 124: 32-41.

http://www.pathguy.com/histo/087.htm

Asthma in ChildrenAsthma in Children

Asthma is the most common chronic Asthma is the most common chronic disorder of childhooddisorder of childhood

Over 9 million children under the age Over 9 million children under the age of 18 in the US have been diagnosed of 18 in the US have been diagnosed with asthma with asthma – The disparity between Black and white The disparity between Black and white

non-Hispanic children is increasingnon-Hispanic children is increasing Asthma morbidity and mortality is Asthma morbidity and mortality is

increasing as wellincreasing as well

The Burden of Asthma in The Burden of Asthma in ChildrenChildren

1 million US children <18 y/o experience 1 million US children <18 y/o experience some degree of disability due to asthma some degree of disability due to asthma – Disabling asthma disproportionately affects Disabling asthma disproportionately affects

Blacks and Hispanics, single-parents, lower SESBlacks and Hispanics, single-parents, lower SES Disabling asthma lead to ~3 weeks of Disabling asthma lead to ~3 weeks of

restrictive activity per year higher than restrictive activity per year higher than other chronic medical conditionsother chronic medical conditions– 9.7 school days/year 9.7 school days/year – ~9.2 physicians contacts/year~9.2 physicians contacts/year

Asthma EtiologyAsthma Etiology

Asthma is a complex traitAsthma is a complex trait– Heritable and environmental factors contribute Heritable and environmental factors contribute

to its pathogenesisto its pathogenesis Multiple interacting genesMultiple interacting genes

– At least 20 distinct chromosomal regions with At least 20 distinct chromosomal regions with linkage to asthma and asthma related traits linkage to asthma and asthma related traits have been identifiedhave been identified

Chromosome 5q – cytokine gene clusterChromosome 5q – cytokine gene cluster ADAM33ADAM33 – bronchial hyperresponsiveness – bronchial hyperresponsiveness PHF11PHF11 – total IgE – total IgE

Hygiene HypothesisHygiene Hypothesis

Rapid rise in atopy and asthma is Rapid rise in atopy and asthma is greatest in developed countries and greatest in developed countries and urban areasurban areas– Cannot be explained by change in Cannot be explained by change in

genetic background but is thought to be genetic background but is thought to be the result of complex interactions the result of complex interactions between genes and the environment between genes and the environment

HistoryHistory

““These observations…could be explained if These observations…could be explained if allergic disease were prevented by infection in allergic disease were prevented by infection in early childhood, transmitted by unhygienic early childhood, transmitted by unhygienic contact with older siblings, or acquired contact with older siblings, or acquired prenatally…Over the past century declining prenatally…Over the past century declining family size, improved household amenities and family size, improved household amenities and higher standards of personal cleanliness have higher standards of personal cleanliness have reduced opportunities for cross-infection in reduced opportunities for cross-infection in young families. This may have result in more young families. This may have result in more widespread clinical expression of atopic widespread clinical expression of atopic disease.”disease.” David Strachan, BMJ, 1989 David Strachan, BMJ, 1989

Allergic Diseases and Autoimmune Allergic Diseases and Autoimmune Diseases are RisingDiseases are Rising

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

Hygiene HypothesisHygiene Hypothesis Environmental Environmental

impact on asthmaimpact on asthma– Farm exposureFarm exposure– Day care/siblingsDay care/siblings– PetsPets– Early infectionsEarly infections

Hygiene HypothesisHygiene Hypothesis

Yazdanbakhsh M, et al. Science 2002; 296: 490-494

Etiological Factors – Gene and Etiological Factors – Gene and EnvironmentEnvironment

Wills-Karp M, et al. Nature Reviews Immunology; 2001; 1: 69-75

Diagnosing AsthmaDiagnosing Asthma

Clinical diagnosis supported by the Clinical diagnosis supported by the certain historical, physical and certain historical, physical and laboratory findingslaboratory findings– History of episodic symptoms of airflow History of episodic symptoms of airflow

obstructionobstruction– Physical: wheeze, hyperinflationPhysical: wheeze, hyperinflation– Laboratory: exhaled nitric oxide (eNO), Laboratory: exhaled nitric oxide (eNO),

spirometryspirometry Exclude other possibilitiesExclude other possibilities

Conditions Mimicking AsthmaConditions Mimicking Asthma

Obstruction of Obstruction of small airwayssmall airways– AspirationAspiration– Chronic lung Chronic lung

disease secondary disease secondary to prematurityto prematurity

– BronchiolitisBronchiolitis– Cystic FibrosisCystic Fibrosis

Obstruction of Obstruction of large airwayslarge airways– Foreign bodyForeign body– Congenital Congenital

malformationsmalformations– Cardiac diseaseCardiac disease– Endobronchial Endobronchial

tumorstumors– Extrabronchial Extrabronchial

obstructionobstruction– PsychogenicPsychogenic

Natural History of AsthmaNatural History of Asthma

Martinez, FD. J Allergy Clin Immunol 1999; 104: S169-74.

Diagnosing Asthma in Young Diagnosing Asthma in Young Children – Asthma Predictive IndexChildren – Asthma Predictive Index >> 4 episodes/yr of 4 episodes/yr of

wheezing lasting wheezing lasting more than 1 day more than 1 day affecting sleep in a affecting sleep in a child with one child with one MAJOR or two MAJOR or two MINOR criteriaMINOR criteria

Major criteriaMajor criteria– Parent or sibling Parent or sibling

with asthmawith asthma– Atopic dermatitisAtopic dermatitis– Aeroallergen Aeroallergen

sensitivitysensitivity Minor criteriaMinor criteria

– Food sensitivityFood sensitivity– Eosinophilia (Eosinophilia (>>4%)4%)– Wheezing apart Wheezing apart

from infectionfrom infection

Adapted from Castro-Rodriquez JA, et al. AJRCCM 2000; 162: 1403

Outcome of Childhood AsthmaOutcome of Childhood Asthma

Phelan PD, et al. J Allergy Clin Immnol 2002; 109: 189-94.

Asthma ClassificationAsthma ClassificationDays with Days with symptomssymptoms

Nights with Nights with symptoms symptoms

PEF or PEF or FEV1FEV1

PEF PEF VariabilityVariability

Mild Mild IntermittentIntermittent

<<2x/week2x/week <<22x/monthx/month >>80%80% <20%<20%

Mild Mild PersistentPersistent

3-6x/week3-6x/week >2x/month>2x/month >>80%80% 20-30%20-30%

Moderate Moderate PersistentPersistent

DailyDaily >1x/week>1x/week >60->60-<80%<80%

>30%>30%

Severe Severe PersistentPersistent

ContinuousContinuous FrequentFrequent <<60%60% >30%>30%

Adapted from Guidelines for the Diagnosis and Management of Asthma-Update on Selected Topics 2002. NIH Publication No. 02-5075.

Pa t

ient

Dea

ths

(%)

Pat

i ent

De a

ths

(%)

Asthma Mortality: Asthma Mortality: Mild Patients Are Also at RiskMild Patients Are Also at Risk

Robertson et al.Robertson et al. Pediatr Pulmonol. Pediatr Pulmonol. 1992;13:95-100.1992;13:95-100.

Patient AssessmentPatient Assessment

00

1010

2020

3030

SevereSevere ModerateModerate MildMild

4040

"Rules of Two" is a trademark of th"Rules of Two" is a trademark of the Baylor Health Care Systeme Baylor Health Care System

Rules of TwoRules of TwoTMTM

Use of a quick-relief inhaler more Use of a quick-relief inhaler more than: than: 2 times per week2 times per week

Awaken at night due to asthma Awaken at night due to asthma symptoms more than: symptoms more than: 2 times per 2 times per monthmonth

Refill of a quick-relief inhaler Refill of a quick-relief inhaler prescription more than: prescription more than: 2 times per 2 times per yearyear

Rel

ativ

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isk

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Rel

ativ

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isk

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Hos

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Hos

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88

77

66

55

44

33

22

11

00

Prescriptions per Person-YearPrescriptions per Person-Year

NoneNone 1-21-2 2-32-3 3-53-5 5-85-8 8+8+0-10-1

ßß22-agonists-agonists

TotalTotal

Age 0-17Age 0-17

TotalTotal

Age 0-17Age 0-17

Inhaled SteroidsInhaled Steroids

Breaking the “Rules of TwoBreaking the “Rules of TwoTMTM” Results in ” Results in Asthma MorbidityAsthma Morbidity

Adapted from Donahue et al. Adapted from Donahue et al. JAMA.JAMA. 1997;277:887-891. 1997;277:887-891.

Goals of TreatmentGoals of Treatment

SLEEPSLEEP LEARNLEARN PLAYPLAY

Key Components of Asthma Key Components of Asthma TherapyTherapy

Assessment and monitoringAssessment and monitoring Pharmacologic therapyPharmacologic therapy ““Trigger” controlTrigger” control Patient educationPatient education

Adapted from NAEPP Practical Guide for the Diagnosis and Management of Asthma. 1997 NIH Pub 97-4053.

Pharmacologic TreatmentPharmacologic Treatment““Controller”Controller”

Long-term ControlLong-term Control““Rescue”Rescue”

Short-actingShort-acting

Mild Mild IntermittentIntermittent

NoneNone ΒΒ22-agonist-agonist

Mild Mild PersistentPersistent

Preferred: low dose inhaled Preferred: low dose inhaled corticosteroid (ICS)corticosteroid (ICS)

ΒΒ22-agonist-agonist

Moderate Moderate PersistentPersistent

Preferred: low-medium dose ICS Preferred: low-medium dose ICS and long-acting and long-acting ΒΒ22-agonist-agonist

ΒΒ22-agonist-agonist

Severe Severe PersistentPersistent

Preferred: low-medium dose ICS Preferred: low-medium dose ICS and long-acting and long-acting ΒΒ22-agonist and -agonist and oral corticosteroids if neededoral corticosteroids if needed

ΒΒ22-agonist-agonist

Adapted from Guidelines for the Diagnosis and Management of Asthma-Update on Selected Topics 2002. NIH Publication No. 02-5075.

Inhaled CorticosteroidsInhaled Corticosteroids Preferred treatment alone or in Preferred treatment alone or in

combination for all persistent categories of combination for all persistent categories of asthmaasthma

Safe when use is monitoredSafe when use is monitored Reduces asthma symptoms, bronchial Reduces asthma symptoms, bronchial

hyperreactivity, exacerbations and hyperreactivity, exacerbations and hospitalizations, need for rescue hospitalizations, need for rescue medicationsmedications

Improves pulmonary function, quality of Improves pulmonary function, quality of lifelife

May prevent airway remodelingMay prevent airway remodeling

ICS Use Lowers Risk of Death ICS Use Lowers Risk of Death from Asthmafrom Asthma

Suissa S et al. N Engl J Med 2000; 343: 332-336

ICS Are More Effective at Decreasing Asthma ICS Are More Effective at Decreasing Asthma Exacerbations Than Anti-leukotriene AgentsExacerbations Than Anti-leukotriene Agents

Results not affected by type of medication, methods, analysis, publication status or funding source. Insufficient evidence in children.* No exacerbations reported

MasperoBaumgartner

BusseHughes (BUD)*

Hughes (FP) Laviolette*

SkalkyWilliamsBleecker

Busse

Fixed EffectsPooled Relative Risk

0.1 -15 -10 -5 0 +5 +10 +15 +10

Relative Risk (95% CI)

Ducharme FM, BMJ 2003; 326: 621

Favors anti-leukotrienes Favors inhaled glucocorticoids

11

Kim

1.61.6

Dose

ICS – Finding the Right BalanceICS – Finding the Right Balance

The range that the risk:benefit ratio is favorable is that at which the wanted effects in the lungs increases steeply with dose while the unwanted systemic effects increase gradually. At higher doses, the increase in risk greatly outweighs the slight remaining increase in benefit. This relationship seems to vary for different inhaled corticosteroids.

Barnes et al, Am J Respir Crit Care Med Vol 157, 00S1-S53, 1998.

Response

Favorable Benefit:Risk Ratio Wanted Effects

Unwanted Effects

Long Term Effects of Budesonide Long Term Effects of Budesonide or Nedocromil On Growthor Nedocromil On Growth

Childhood Asthma Management Program Research Group N Engl J Med 2000; 343: 1054-63.

Adult Height is not Affected by ICS Adult Height is not Affected by ICS UseUse

Agertoft L, Pedersen S. N Engl J Med 2000; 343: 1064-69.

Not All ICS are the SameNot All ICS are the Same

PotencyPotency Systemic absorptionSystemic absorption DosingDosing

Doubling doses of ICS – Twice as Doubling doses of ICS – Twice as Good?Good?

FitzGerald JM, et al. FitzGerald JM, et al. – No significant difference in exacerbation No significant difference in exacerbation

outcome when ICS doubled outcome when ICS doubled – Possible explanationsPossible explanations

Not frequent enough useNot frequent enough useOnset of ICS slower than systemic Onset of ICS slower than systemic

corticosteroidscorticosteroidsAirflow limitations affect ICS deliveryAirflow limitations affect ICS deliveryDose increase insufficientDose increase insufficient

Adapted from FitzGerald JM, et al. Thorax. 2004; 59:550-556.

Leukotriene Receptor AntagonistsLeukotriene Receptor Antagonists

Alternative therapy for mild-Alternative therapy for mild-persistent asthma as well as persistent asthma as well as alternative combination therapy with alternative combination therapy with ICS for moderate persistent asthmaICS for moderate persistent asthma

SafeSafe Easy to administerEasy to administer Improves asthma symptom free-Improves asthma symptom free-

days, but less than ICSdays, but less than ICS

ICS vs. MontelukastICS vs. Montelukast

Busse W, et al. J Allergy Clin Immunol 2001; 107: 461-468.

Combination TherapiesCombination Therapies Combination therapies work better than Combination therapies work better than

increasing the dose of ICSincreasing the dose of ICS

Condemi JJ, et al. Ann Allergy Asthma Immunol 1999;82:383–389.

Combination Therapy of ICS and Salmeterol is Combination Therapy of ICS and Salmeterol is Better Than Increasing the ICS doseBetter Than Increasing the ICS dose

Studies not individually powered to examine exacerbation rates.

IndGreening

WoolcockKelsenMurray

KalbergCondemi

Van Noord (LD)Van Noord (HD)

Vermetten

Fixed EffectsRandom Effects

-20 -15 -10 -5 0 +5 +10 +15 +20Treatment Difference (%)

Shrewsbury et al. Br Med J. 2000;320:1368-1373.

Favors increasing ICS Favors adding salmeterol

Montelukast and ICSMontelukast and ICS

Laviolette M, et al. Am J Respir Crit Care Med 1999; 160: 1862-1868

Salmeterol and ICS vs. Salmeterol and ICS vs. Montelukast and ICSMontelukast and ICS

Nelson HS, et al. J Allergy Clin Immunol, 2000; 106: 1088-1095

PharmacogeneticsPharmacogenetics

Study of the role of genetic Study of the role of genetic determinants in the variable determinants in the variable response to therapy response to therapy

The future of asthma treatmentThe future of asthma treatment

Other Management IssuesOther Management Issues

Environmental controlEnvironmental control– ““Safe” roomSafe” room

Diet Diet – Infant feedingInfant feeding– SodiumSodium– Fatty acidsFatty acids– AntioxidantsAntioxidants

Is Environmental Control Helpful?Is Environmental Control Helpful?

Single allergen Single allergen reduction not effectivereduction not effective

“…Treatment by means of allergen avoidance requires the definition of what patients are allergic to, and additional measures beyond the use of mattress covers and education” Thomas Platts-Mills

http://health.allrefer.com/health/asthma-common-asthma-triggers.html

Tailored Environmental Intervention Tailored Environmental Intervention

Morgan et al, 2004Morgan et al, 2004 Randomized, controlled trial of Randomized, controlled trial of

environmental interventionenvironmental intervention Intervention resulted inIntervention resulted in

– Reduction in asthma symptoms, disruption in Reduction in asthma symptoms, disruption in caretakers plans, caretaker’s and child’s sleep, caretakers plans, caretaker’s and child’s sleep, asthma-related visits to the ER or clinicasthma-related visits to the ER or clinic

– Reduction in asthma symptoms were Reduction in asthma symptoms were correlated to reduction in allergenscorrelated to reduction in allergens

No difference in reduction of allergens in No difference in reduction of allergens in homes with carpets or without carpetshomes with carpets or without carpets

Tailored Environmental Control Tailored Environmental Control Reduces Asthma SymptomsReduces Asthma Symptoms

Morgan WJ, et al. N Engl J Med 2004; 351: 1068-80.

Air Filters and AsthmaAir Filters and Asthma

McDonald E, et al. Chest 2002; 1535-42.

Diet and AsthmaDiet and Asthma

High sodium diet may result High sodium diet may result in adverse effects on airway in adverse effects on airway reactivity in patients with reactivity in patients with asthmaasthma– No recommendation to No recommendation to

implement low salt dietsimplement low salt diets Potassium and Magnesium Potassium and Magnesium

effect unclear effect unclear Tartazine exclusion not Tartazine exclusion not

helpful except perhaps those helpful except perhaps those with proven sensitivitywith proven sensitivity

Diet and AsthmaDiet and Asthma Breast feedingBreast feeding

– Exclusive breast feeding > 4 monthsExclusive breast feeding > 4 months Protective against recurrent wheezeProtective against recurrent wheeze Higher odds of asthma in children who Higher odds of asthma in children who

are atopic and have a mother with are atopic and have a mother with asthmaasthma

Maternal avoidance diets during Maternal avoidance diets during pregnancy does not affect pregnancy does not affect incidence of asthmaincidence of asthma

Utilization of protein hydrolyzed Utilization of protein hydrolyzed formulas have not been shown to formulas have not been shown to reduce incidence of asthmareduce incidence of asthma

Probiotics supplementation has Probiotics supplementation has demonstrated decrease in atopy, demonstrated decrease in atopy, but asthma is unknownbut asthma is unknown

Diet and AsthmaDiet and Asthma Polyunsaturated fatty acidsPolyunsaturated fatty acids

– Omega 3’s vs. Omega 6’sOmega 3’s vs. Omega 6’s Omega 6 fatty acids, present in animal fat, Omega 6 fatty acids, present in animal fat,

metabolized to arachidonic acid generating potent metabolized to arachidonic acid generating potent inflammatory mediators and broncho-constricting inflammatory mediators and broncho-constricting agentsagents

Omega 3 fatty acids, found particularly in fatty fish Omega 3 fatty acids, found particularly in fatty fish are metabolized to eicosapentaenoic acid (EPA) and are metabolized to eicosapentaenoic acid (EPA) and docosahexaenoic aciddocosahexaenoic acid

– May competitively inhibit the use of arachidonic acid as May competitively inhibit the use of arachidonic acid as a substrate for the production of pro-inflammatory a substrate for the production of pro-inflammatory mediators such as prostaglandins and leukotrienesmediators such as prostaglandins and leukotrienes

– Theoretical benefit to lung function, but not Theoretical benefit to lung function, but not conclusively proven in studiesconclusively proven in studies

Trans fatty acids associated with prevalence of Trans fatty acids associated with prevalence of asthma, allergic conjunctivitis, and atopic asthma, allergic conjunctivitis, and atopic eczemaeczema

Diet and AsthmaDiet and Asthma

AntioxidantsAntioxidants– Epidemiological evidence Epidemiological evidence

suggests that antioxidants have a suggests that antioxidants have a role in asthmarole in asthma

– Randomized trialsRandomized trials No current role for Vitamin C in the No current role for Vitamin C in the

treatment of asthmatreatment of asthma Vitamin E supplementation provides Vitamin E supplementation provides

no additional benefit to standard no additional benefit to standard treatment of asthmatreatment of asthma

No substantiated role for No substantiated role for ΒΒ-carotene -carotene supplementation in asthmasupplementation in asthma

Asthma EducationAsthma Education

Self management education Self management education associated with:associated with:– Improvements in airflowImprovements in airflow– Improvements in self-efficacy scalesImprovements in self-efficacy scales– Reductions in school absenceReductions in school absence– Reduction in days of restricted activityReduction in days of restricted activity– Reduction in emergency room visitsReduction in emergency room visits

SummarySummary

Asthma is a disease of chronic airway Asthma is a disease of chronic airway inflammation; thus, inhaled inflammation; thus, inhaled corticosteroids is the preferred corticosteroids is the preferred pharmacologic therapypharmacologic therapy

Persistent asthma (those who break Persistent asthma (those who break the “rules of two”) need a controller the “rules of two”) need a controller medicationmedication

Children with asthma should all be Children with asthma should all be able to sleep, learn, and playable to sleep, learn, and play