Asthma

Mark A. Brown, MDMark A. Brown, MDArizona Respiratory CenterArizona Respiratory Centermabrown@arc.arizona.edumabrown@arc.arizona.edu

Tucson Pediatric Pulmonary Tucson Pediatric Pulmonary CenterCenter

Definition

• Intermittent lower-airway obstruction Intermittent lower-airway obstruction that is reversible either spontaneously that is reversible either spontaneously or as the result of treatmentor as the result of treatment

– Inflammation and edemaInflammation and edema

– Bronchial smooth-muscle spasmBronchial smooth-muscle spasm

– Mucous pluggingMucous plugging

Definitions

• Asthma exacerbation: symptoms Asthma exacerbation: symptoms that require a change in that require a change in medication from baselinemedication from baseline

• Status asthmaticus: increasingly Status asthmaticus: increasingly severe asthma that is not severe asthma that is not responsive to drugs that are responsive to drugs that are usually effectiveusually effective

Epidemiology

• 10% of children in the US: 5 million 10% of children in the US: 5 million children under the age of 18children under the age of 18

• Prevalence is increasingPrevalence is increasing

• Asthma morbidity and mortality is Asthma morbidity and mortality is increasingincreasing

• 50% have family history of asthma, 50% have family history of asthma, rhinitis, eczematous dermatitis, or rhinitis, eczematous dermatitis, or urticariaurticaria

Onset of Symptoms in Children With Asthma

McNicol and Williams. BMJ 1973;4:7-11; Wainwright et al. Med J Aust 1997;167:218-222.

30%

20% 30%

20%

1-2 years

>3 years

<1 year

2-3 years

Natural History of Childhood Asthma

Age (Years)

Wh

eezi

ng

Pre

vale

nce

Non-atopicwheezers

Transient earlywheezers

IgE-associatedwheeze/asthma

0 3 6 11

Martinez. J Allergy Clin Immunol 1999;104:S169-S174.

Asthma Prevalence in US Children

SOURCE: US EPA (NCHS, 2006-2010).

Asthma Ambulatory Visits

Akinbami LJ, et al. Pediatrics, 2009; 123:S131-S145Akinbami LJ, et al. Pediatrics, 2009; 123:S131-S145

Childhood Asthma Deaths

Akinbami LJ, et al. Pediatrics, 2009; 123:S131-S145Akinbami LJ, et al. Pediatrics, 2009; 123:S131-S145

Arizona vs. US Asthma Age-Adjusted Mortality Rate 1991-98

0

0.5

1

1.5

2

2.5

3

1993 1994 1995 1996 1997 1998

Arizona

United States

Dea

ths/

100,

000

popu

lati

onD

eath

s/10

0,00

0 po

pula

tion

Risk Factors• Previous attack with:Previous attack with:

• Severe unexpected or rapid Severe unexpected or rapid deteriorationdeterioration

• Respiratory Failure (ICU/Intubation)Respiratory Failure (ICU/Intubation)

• Seizure or loss of consciousnessSeizure or loss of consciousness

• Recent use of oral steroids or Recent use of oral steroids or decrease in ICSdecrease in ICS

• Frequent use of short acting Frequent use of short acting -agonist-agonist

Risk Factors

• Two or more hospitalizations in Two or more hospitalizations in the last yearthe last year

• Hospitalization or ED in the last Hospitalization or ED in the last monthmonth

• 3 or more ED visits in the last 3 or more ED visits in the last yearyear

Risk Factors

• PsychosocialPsychosocial

– Denial or failure to perceive severityDenial or failure to perceive severity

– DepressionDepression

– NonadherenceNonadherence

– Dysfunctional familyDysfunctional family

– Inner-city residentInner-city resident

Busse and Lemanske. N Engl J Med. 2001;344:350-62.

Inflammation in Mild Asthma

Subject Without Asthma Patient With Mild Asthma

CXR

Chetta et al. Chest. 1997;111:852-7.

*P<.001, healthy subjects vs patients with asthma.

Airway Remodeling

P<.01

*

Severe Moderate Mild Healthy(n=6) (n=14) (n=14) (n=8)

SubepithelialLayerThickness (µm)

30

20

10

0

P<.003

Rel

ativ

e R

isk

of

Rel

ativ

e R

isk

of

Hos

pit

aliz

atio

nH

osp

ital

izat

ion

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

Frequent Use of B2 Agonists Increased Likelihood of Asthma-related Hospitalizations

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

B cellB cell

IgEIgE

dendriticdendriticcellcell

ICAM-1/3ICAM-1/3

IL-1IL-1

CD4CD4

antigen presentationantigen presentation

IL-12IL-12

CD8CD8

mastmastcellcell

MCP-3MCP-3

IL-5IL-5

IL-6IL-6

NCFNCFMIP-1MIP-1

LTB-4LTB-4

SCFSCF

IL-3IL-3

IL-14IL-14

tryptasetryptase

GM-CSFGM-CSF

LTC-4LTC-4

RANTESRANTES

TNF-TNF-

IL-8IL-8

eotaxineotaxin

IL-13IL-13

LTE-4LTE-4

IFN-IFN-

PGDPGD22histaminehistamine

IL-1IL-1

PAFPAF

chemokineschemokines

LTD-4LTD-4

IL-4IL-4

neuroneneurone

neurokininsneurokinins myofibroblastmyofibroblast

GM-CSFGM-CSFC-kitC-kit

IL-6IL-6Th-2Th-2

SCFSCF

GM-CSFGM-CSF

IL-13IL-13

TNF-TNF-

IL-1IL-1

IgEIgEIL-10IL-10

IL-4IL-4

IL-3IL-3

IL-5IL-5

IL-6IL-6

Th-1Th-1TNF-TNF-

IL-2IL-2

IFN-IFN-

Th-0Th-0

GM-CSFGM-CSF

IL-2IL-2

IFN-IFN-

IL-4IL-4

basophilbasophil

histaminehistaminecytokinescytokines

LTC-4LTC-4

LTD-4LTD-4

LTE-4LTE-4

IL-13IL-13

IL-4IL-4

PGSPGS

IgEIgEGM-CSFGM-CSF PAFPAF

proteaseprotease

IL-6IL-6 IL-8IL-8

neutrophilneutrophil

TNF-TNF-TGF-TGF-11

PAFPAF

LTD-4LTD-4

TXATXA

22

IL-1IL-1

IL-6IL-6

MPOMPO

O speciesO speciesBIPBIP

IL-8IL-8

LTB-4LTB-4

LTC-4LTC-4

endothelial cellendothelial cell

adhesion moleculesadhesion molecules

GM-CSFGM-CSFICAM-1ICAM-1

IL-4IL-4

L-selectinL-selectinPGSPGS

TNF-TNF-

ET-2ET-2

ET-1ET-1

IL-1IL-1

G-CSFG-CSF IL-6IL-6

fibroblastfibroblast

TGF-TGF-

PDGFPDGF

GM-CSFGM-CSFIL-1IL-1

IL-6IL-6

MIP-1MIP-1 RANTESRANTESCOLLAGEN I, II, COLLAGEN I, II,

VV

IL-8IL-8

MCP-1MCP-1

PGEPGE22

collagenasecollagenaseICAM-1ICAM-1 IL-11IL-11

SCFSCF

VCAM-1VCAM-1

eosinophileosinophil

LTC-4LTC-4

MCP-3MCP-3

IL-4IL-4

IL-6IL-6

IL-10IL-10

LTD-4LTD-4

OO22

PDGF-BPDGF-B

ECPECP

IL-5IL-5

IL-8IL-8

HB-EGFHB-EGF

TGFTGF

GM-CSFGM-CSF

TXB-2TXB-2

RANTESRANTES

TNF-TNF-

IL-3IL-3

IL-1IL-1

EDPEDP

MBPMBP

15-HETE15-HETEIL-2IL-2

PAFPAF

0 species0 species

IFN-IFN-

IL-13IL-13

MIP-1MIP-1

CR-3CR-3EDNEDN

ICAM-1ICAM-1

MCP-2MCP-2

MCP-1MCP-1

macrophagemacrophage

IL-IL-

IL-5IL-5

MCP-3MCP-3

MIP-1MIP-1

iNOSiNOS

PAFPAF

IL-10IL-10

LTB-4LTB-4

EAFEAFIL-1IL-1

TNF-TNF-

IL-6IL-6

IL-1IL-1

eotaxineotaxin

PGEPGE22

IL-12IL-12IFN-IFN-

RANTESRANTES

IL-3IL-3

GM-CSFGM-CSF

0 species0 species

IL-8IL-8proteaseprotease

epithelial cellepithelial cell

MCP-1MCP-1

IL-5IL-5IL-3IL-3

15-LD15-LD

SLPISLPI

NEPNEP

COXCOX22

iNOSiNOS

15-LT515-LT5

PGFPGF22

PGEPGE22

IGF-IIGF-I

CGRPCGRP

FGFFGFIL-16IL-16

IL-8IL-8CPLACPLA22adhesion moleculesadhesion molecules

GRO-GRO-NONO

GM-CSFGM-CSF

MCP-2MCP-2

RANTESRANTES

IL-1IL-1

TNF-TNF-

IL-6IL-6

IL-11IL-11

ET-1ET-1

VIPVIP

9/13 HODE9/13 HODE

15-HETE15-HETE

eotaxineotaxinIL-17IL-17PDGFPDGF

IL-10IL-10MIP-1MIP-1

ICAM-1ICAM-1

RANTESRANTES

smoothsmoothmuscle cellmuscle cell

cytokinescytokines

eotaxineotaxin

GM-CSFGM-CSF

IL-8IL-8

MCP-1MCP-1PGEPGE22

MCP-2MCP-2

MCP-3MCP-3

Mediator releasemodified

monocytemonocyte

IL-5IL-5

MCP-3MCP-3

MIP-1MIP-1

NONO

IL-1IL-1

TNF-TNF-

eotaxineotaxin

PGEPGE22

IFN-IFN-

RANTESRANTES

IL-3IL-3 GM-CSFGM-CSF

0 species0 species

IL-2IL-2

TXATXA22

IL-4IL-4

IL-8IL-8

cytokinescytokinesIL-6IL-6 IL-10IL-10 IL-12IL-12

LTB-4LTB-4LTC-4LTC-4 ICAM-1ICAM-1

G-CSFG-CSF

IFN-IFN-

Effects of Corticosteroids on Inflammatory Cells

ICS May Prevent Death From Asthma

Suissa et al. N Engl J Med. 2000;343:332-6.

Rate Ratio for Death From Asthma

Number of Canisters of Inhaled Corticosteroids Used in the Year Before Death From Asthma

0.0

0.5

1.0

1.5

2.0

2.5

2 4 6 8 10 12

Effects of Inhaled Corticosteroidson Inflammation

Pre- and post- 3 month treatment with budesonidePre- and post- 3 month treatment with budesonide(BUD) 600 mcg BID; E = epithelium, BM = basement membrane(BUD) 600 mcg BID; E = epithelium, BM = basement membrane

Laitinen.Laitinen. J Allergy Clin Immunol. J Allergy Clin Immunol.1992;90:32-42. 1992;90:32-42.

Budesonide Nedocromil Placebo

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

No./100 Person-Year

Greater reductions in the need for emergency care

Health Resource Utilization

0

10

20

30

2.54.44.3

Hospitalizations

P=.0412

16

22

Urgent Care Visits

P<.001

P=.02

CAMP = Childhood Asthma Management Program.

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

CAMP: ICS Reduced Oral Prednisone Use

First Course of Prednisone

Budesonide

Nedocromil

Placebo

0 1 2 3 4Time (y)

1.00

0.75

0.50

0.25

0.00

P<.001 budesonide vs placeboP=.32 nedocromil vs placebo

Cumulative Probability

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

0

25

50

75

100

125

Prednisone Courses

No./100 Person-Year

P<.001P=.01

122

102

70

Budesonide Nedocromil Placebo

Prednisone Use

Corticosteroid Dose Response Curves for Various Outcomes

Symptoms (reduction)FEV1 (increase)Exercise (FEV1) (increase)Nitric oxide (reduction)FEF25-75% (increase)

100

80

60

40

20

0 600200 400 800Daily Dose of Budesonide (g)

% of Maximum

Barnes et al. Am J Respir Crit Care Med. 1998;157:S1-S53.

0

Lower Doses Are Associated With Fewer Risks

Response

Pedersen et al. Allergy. 1997;52:1-34.Dose

Therapeutic Effects

Favorable Benefit:Risk Ratio

Undesirable Effects

Childhood Asthma Management Program Research Group. Childhood Asthma Management Program Research Group. N Engl J Med N Engl J Med 2000;343:1054-1063.2000;343:1054-1063.

00

4.54.5

5.05.0

6.06.0

6.56.5

00 11 22 33 44Time (yr)Time (yr)

cm/yrcm/yr

Standing-Height VelocityStanding-Height Velocity

5.55.5

00

130130

135135

145145150150

00 11 22 33 44Time (yr)Time (yr)

308 294308 294 293 289 280 293 289 280309 303309 303 293 284 271 293 284 271414 400414 400 392 386 379 392 386 379

cmcm

Standing HeightStanding Height

140140

BudesonideBudesonideNedocromilNedocromilPlaceboPlacebo

155155160160

BudesonideBudesonideNedocromilNedocromilPlaceboPlacebo

Number of Patients Remaining in the Study Number of Patients Remaining in the Study

Long Term Effects of Budesonide and Nedocromil On Growth

294294 286286 288 275 288 275 303303 291291 278 266 278 266 400400 388 388 379 370 379 370

= Girls= Girls

= Boys= Boys

Agertoft L & Pedersen S. NEJM 343:1064, 2000Agertoft L & Pedersen S. NEJM 343:1064, 2000

Predicted and Measured Adult Height

Important Additional Steps

• Asthma educationAsthma education• Triggers, Adherence, Follow-upTriggers, Adherence, Follow-up

• Identify and treat comorbiditiesIdentify and treat comorbidities• Allergies, Sinus Disease, RefluxAllergies, Sinus Disease, Reflux

• Address Barriers to CareAddress Barriers to Care

Childhood Asthma

• Serious, common diseaseSerious, common disease

• InflammationInflammation

• Inhaled steroids are effectiveInhaled steroids are effective

• Environmental and social factors Environmental and social factors are very importantare very important

He who knows and knows that he knows is conceited; avoid him. He who knows not and knows not that he knows not is a fool; instruct him.He who knows and knows not that he knows is asleep; awaken him.But he who knows not and knows that he knows not is a wise man; follow him.

— Arab proverb