Asthma

1o A|r |s numan, 1o Not Wheeze D|v|ne

Meyer 8alLer Mu, l8CC,lCC
MounL Slnal PosplLal
unlverslLy of 1oronLo


D|sc|osure Statements
l have served on advlsory boards for:
AsLraZeneca, ClaxoSmlLhkllne, novarus, 1akeda
l have recelved honorarla for speaklng from:
Abbou, AsLraZeneca, 8oehrlnger-lngelhelm, Merck,
novarus, 1akeda
l have no nanclal lnLeresLs ln any pharmaceuucal
company
ln Lhe pasL 2 years:
Cb[ecnves
1o appreclaLe Lhe rlslng prevalence and rlsk facLors for
asLhma
1o undersLand Lhe paLhophyslology of Lhe dlsease
1o learn an approach Lo poorly conLrolled asLhma
1o undersLand Lhe ClnA sLraLegy for LreaLmenL of
asLhma
1o be able Lo assess, LreaL, and prevenL asLhma
exacerbauons

G
IN
A
lobal
itiative for
sthma
Clobal lnluauve for AsLhma
Dehn|non of Asthma
A chronlc lnammaLory dlsorder of Lhe alrways
Many cells and cellular elemenLs play a role
Chronlc lnammauon ls assoclaLed wlLh alrway
hyperresponslveness LhaL leads Lo recurrenL
eplsodes of wheezlng, breaLhlessness, chesL
ughLness, and coughlng
Wldespread, varlable, and oen reverslble alrow
llmlLauon


Source: Peter J. Barnes, MD
Asthma Inammanon: Ce||s and Med|ators

INDUCLkS
A||ergens, chem|ca| sens|nzers,
a|r po||utants, v|rus |nfecnons

INILAMMA1ICN

1kIGGLkS
A||ergens,
exerc|se,
co|d a|r, SC
2

parncu|ates
SM1CMS
Cough, wheeze,
chest nghtness,
dyspnea
A|rway
hyperrespons|veness
A|row ||m|tanon
8arnes !. 8t I cllo lbotmocol 1996
Pathophysiology of Asthma
Asthma reva|ence: USA
k|sk of Deve|op|ng Asthma |n the USA
Asthma nea|th Care Lncounters: USA
k|sk factors assoc|ated w|th the
deve|opment of asthma
PosL facLors
Ceneuc
ALopy
AP8
Cender
CbeslLy
LnvlronmenLal facLors
Alr polluuon
lndoor
CuLdoor
lndoor allergens
Anlmal dander
Cockroaches
uusL mlLes
lungl
Cccupauonal sensluzers
CuLdoor allergens
8esplraLory lnfecuons
Smoklng
Acuve
asslve
Asthma: D|agnos|s
PlsLory and pauern of sympLoms
hyslcal examlnauon
MeasuremenL of lung funcuon
eak explraLory ow (Ll)
lorced explraLory volume ln 1 second (lLv
1
)
8everslblllLy LesL
ulurnal varlablllLy
Lvaluauon of alrway responslveness
Lxerclse challenge
MeLhachollne challenge
8ouleL L, eL al. coo kesplt I 2001
Is |t asthma?
SympLoms vary over ume and ln severlLy
8reaLhlessness
ChesL ughLness
Coughlng
Wheezlng
SympLoms occur or worsen aL nlghL or aer
exposure Lo Lrlggers
Colds go Lo Lhe chesL" or Lake >10 days Lo clear
kevers|b|e and var|ab|e a|row ||m|tanon
8everslblllLy of alrways' obsLrucuon
lncreased lLv1>12 13-20 mlnuLes aer lnhallng

2
-agonlsL
varlablllLy of alrways' obsLrucuon
Ll varles beLween mornlng and evenlng by > 20
decreased Ll >10 aer 6 mlnuLes of exerclse
Canadlan Culdellnes
Clobal lnluauve for AsLhma
Measur|ng A|rway kespons|veness
Levels of Asthma Control
(Assess patient impairment)

Characteristic
Controlled
(All of the following)
Partly controlled
(Any present in any week)
Uncontrolled
Daytime symptoms
Twice or less
per week
More than
twice per week
3 or more
features of
partly
controlled
asthma
present in
any week

Limitations of
activities
None Any
Nocturnal
symptoms /
awakening
None Any
Need for rescue /
reliever treatment
Twice or less
per week
More than
twice per week
Lung function
(PEF or FEV
1
)
Normal
< 80% predicted or
personal best (if
known) on any day
Assessment of Future Risk (risk of exacerbations, instability, rapid
decline in lung function, side effects)
Global Initiative for Asthma
D|mcu|t]Severe]kefractory Asthma
Muluple denluons, noL sLandardlzed
ulmculL Lo LreaL
unconLrolled due Lo facLors oLher Lhen asLhma lLself
Severe refracLory
unconLrolled desplLe approprlaLe dlagnosls and auenuon
Lo reverslble facLors
Lxacerbauons are promlnenL feaLure of all causes of
unconLrolled asLhma
uene fuLure rlsk
D|mcu|t to Contro| Asthma
conrm dlagnosls

A|| 1hat Wheezes |s Not Asthma:
D|erenna| D|agnos|s of Asthma
osL-lnfecuous cough
osL-nasal drlp
CasLroesophageal
reux dlsease
Chronlc obsLrucuve
pulmonary dlsease
PearL fallure
CongenlLal
malformauon
- Anglna
- lorelgn body
- Lung cancer
- Pypervenulauon
syndrome
- vocal cord dysfuncuon
oor|y Contro||ed Asthma
conrm dlagnosls
check adherence
revlew Lechnlque

oor|y Contro||ed Asthma
conrm dlagnosls
check adherence
revlew Lechnlque
quesuon exposures/envlronmenL
allergens, lrrlLanLs, sensluzers


8efore
10 MlnuLes Aer
Allergen Challenge
ko|e of Atopy
Cha||enges w|th env|ronmenta| contro|
Mu|np|e eects of smok|ng |n asthma
Thomson NC et al. ERJ 2004;24:822-33.
oor|y Contro||ed Asthma
conrm dlagnosls
check adherence
revlew Lechnlque
quesuon exposures/envlronmenL
allergens, lrrlLanLs, sensluzers
condluons LhaL worsen asLhma
CL8u, slnus dlsease


Prevalence of GERD in Asthma
0
10
20
30
40
50
60
Sx
No Sx
P
e
r
c
e
n
t

Overall population Documented GER
90 pts
FEV1 66.7 +/-22.5
M:F 41:49
Age 54.3 +/-16
Kiljander TO et al. CHEST 2004;126:1490-4.
GERD found in
36% of asthmatics
Let's |ook at the nose
up Lo 80 of asLhmaucs have
A8
A8 alone ls a rlsk facLor for:
uevelopmenL of asLhma
Lu vlslLs for asLhma
1reaLmenL of Lhe nose:
8educes 8P8
uecreases exacerbauons
oor|y Contro||ed Asthma
conrm dlagnosls
check adherence
revlew Lechnlque
quesuon exposures/envlronmenL
allergens, lrrlLanLs, sensluzers
condluons LhaL worsen asLhma
CL8u, slnus dlsease
drugs
8eLa blockers, nSAluS
obeslLy


1. Farah CS, et al. CHEST 2011;140:659-66.
2. Scott HA, et al. Eur Respir J 2011;38:594-602.
Cbes|ty |s a Determ|nant of Asthma Contro|
-Following treatment BMI predicts ACQ-5 independent of airway
inflammation, or BHR
1
-Positive correlation between obesity and sputum PMNs in women

r= 0.58, p<0.001 Rr= 0.22, p=0.14
oor|y Contro||ed Asthma
conrm dlagnosls
check adherence
revlew Lechnlque
quesuon exposures/envlronmenL
allergens, lrrlLanLs, sensluzers
condluons LhaL worsen asLhma
CL8u, slnus dlsease
drugs
beLa-blockers, nSAlus
CbeslLy
CSA
compllcauons of asLhma
A8A
Churg-SLrauss vascullus
1reatment Strategy
ldenufy and avold Lrlggers LhaL aggravaLe asLhma
Achleve conLrol by selecung approprlaLe medlcauon
8egularly monlLor and ad[usL medlcauon as requlred
uevlse an acuon plan for Lhe managemenL of
exacerbauons
LducaLe pauenLs Lo manage Lhelr condluon
8ouleL L, eL al. cMAI 1999
controlled
partly controlled
uncontrolled
exacerbation
LEVEL OF CONTROL
maintain and find lowest
controlling step
consider stepping up to
gain control
step up until controlled
treat as exacerbation
TREATMENT OF ACTION
TREATMENT STEPS
REDUCE INCREASE
STEP
1
STEP
2
STEP
3
STEP
4
STEP
5
R
E
D
U
C
E

I
N
C
R
E
A
S
E

Global Initiative for Asthma
Shaded green - preferred controller options
TO STEP 3 TREATMENT,
SELECT ONE OR MORE:
TO STEP 4 TREATMENT,
ADD EITHER

Lects of ICS on Inammanon
Pre- and post-3month treatment with budesonide (BUD) 600 mcg b.i.d.
Laitinen LA, et al. J Allergy Clin Immunol. 1992;90:32-42.
Estimate Comparative Daily Dosages for
Inhaled Glucocorticosteroids by Age
Drug

Low Daily Dose (g) Medium Daily Dose (g) High Daily Dose (g)
> 5 y Age < 5 y > 5 y Age < 5 y > 5 y Age < 5 y
Beclomethasone 200-500 100-200 >500-1000 >200-400

>1000 >400

Budesonide

200-600 100-200

600-1000 >200-400 >1000 >400
Budesonide-Neb
Inhalation Suspension
250-500 500-1000 >1000
Ciclesonide 80 160 80-160 >160-320 >160-320 >320-1280 >320
Flunisolide 500-1000 500-750 >1000-2000 >750-1250 >2000 >1250
Fluticasone 100-250 100-200 >250-500 >200-500 >500 >500
Mometasone furoate 200-400 100-200 > 400-800 >200-400 >800-1200 >400
Triamcinolone acetonide 400-1000 400-800 >1000-2000 >800-1200 >2000 >1200
Global Initiative for Asthma
Lect of ICS on ILV1 vs Duranon of
Asthma Symptoms 8efore kx
0
1
2
3
4
5
6
7
8
9
A
n
n
u
a
l

c
h
a
n
g
e

i
n

F
E
V
1

(
%
)

<2 2-3 3-5 >5
Years of symptoms prior to budesonide therapy Agertoft L, Pedersen S. Respir Med 1994;88:373-81.
Bronchoconstriction
Mediator Release
Edema
Secretions
Cough
Cellular Proliferation
Extracellular Matrix
Increase

Cell Recruitment
Epithelial Damage
Early Structural Changes
Acute
Response
Airway
Remodeling
Chronic
Inflammation
Adapted from Bousquet et al. Am J Respir Crit Care Med 2000; 161: 1720-1745.
Change |n ILV1 w|th Age:
Asthmancs vs Norma|
0.3
0.5
0.7
0.9
1.1
1.3
1.5
1.7
20 30 40 50 60 70 80
Age (yrs)
H
e
i
g
h
t
-
A
d
j
u
s
t
e
d

F
E
V
1

(
L
)

Male Nonsmokers
No asthma (n=5480)
Asthma (n=314)
Lange P et al. NEJM;1998:339:1194-1200.
No ICS ICS x 10 yrs
-51/ml/yr -25 ml/yr
p<0.001
Thorax 2006;61:100-4.
Number
per year
|acebo 200
0.0 -
0.6 -
0.8 -
1.0 -
0.2 -
0.4 -
200 + Cxeze
0.77
0.29
0.34
C'8kNL M, et a|. Am I kesp|r Cr|t Care Med 2001: 164:1392-7
C1IMA 1r|a|: Group A
Compared to doub||ng the dose of ICS,
add|ng a LA8A to |ow dose ICS:
reduced dayume SA8A needs
decreased nocLurnal sympLoms
lmproved quallLy of llfe
lncreased lLv1
lncreased mornlng and evenlng Ll8s
reduces mlld and severe exacerbauons
Morning Post-dose FEV
1

Weeks
A
M

P
o
s
t
-
d
o
s
e

F
E
V
1

(
L
)

(
M
e
a
n

C
h
a
n
g
e

f
r
o
m

B
a
s
e
l
i
n
e
)

*p 0.001
0
0.1
0.2
0.3
0.4
0.5
0 1 4 8 12 Endpoint
FP/Salm 100/50
FP 100mcg + Montelukast 10mg
*
*
* *
*
Nelson HS et al JACI 2000;106:1088-95.
Ann-IgL 1herapy |n Asthma
Humbert M, et al. Allergy 2005;60:309-16.
ko|e of Add-on Cma||zumab
8ronch|a| 1hermop|asty
3 LreaLmenL sesslons
locallzed radlofrequency
pulse
Can lncrease exacerbauons
ln Lhe shorL Lerm
uecreases exacerbauons
long Lerm
no slgnlcanL eecLs on
sympLoms or l1s
450
400
Tiotropium in asthma:
FEV
1
response over time (Week 24)
0 0.5 1.0 2.0 3.0
0
50
100
150
200
250
300
350
F
E
V
1

[
m
l
]

c
h
a
n
g
e

f
r
o
m

b
a
s
e
l
i
n
e

All on top of ICS+LABA
Time postdosing (h)
Placebo Tiotropium 5g
500
**
**
**
*
*
*P<0.05; **P<0.01
Error bars represent standard errors
Kerstjens et al. NEJM 2012;367:1198-1207.

A1S Consensus for Severe Asthma
Ma[or CrlLerla
1reaLmenL wlLh near consLanL (>30/yr) CCS
need for LreaLmenL wlLh hlgh dose lCS
Mlnor CrlLerla
need for addluonal dally conLroller LreaLmenL
LA8A, L18A, or Lheophylllne producL
8equlremenL of SA8A dally or near dally
erslsLenL alrow obsLrucuon
lLv1<80 predlcLed or dlurnal Ll8 varlablllLy> 20
Cne or more asLhma urgenL care vlslLs per year
> 3 oral sLerold bursLs per year
rompL deLerlorauon wlLh < 23 drop ln lCS or CCS
near-faLal asLhma ln Lhe pasL
American Thoracic Society AJRCCM 2000;162:2341-51.
- Need 1 major or two minor criteria
- Patient compliant
otenna| Asthma henotyp|ca| Categor|es
Cllnlcal/hyslologlc
SeverlLy dened
Lxacerbauon prone
uened by chronlc
obsLrucuon
1reaLmenL reslsLanL
uened by age of onseL
8esponse Lo Lherapy


8elaLed Lo 1rlggers
ASA or nSAlu sensluve
LnvlronmenLal allergens
Cccupauonal lrrlLanLs
Menses
Lxerclse
lnammaLory
henoLypes
Loslnophlllc
neuLrophlllc
aucl-granulocyuc
Wenzel SE. Lancet 2006;368:804-13.
Inammatory henotypes
unLreaLed asLhma has hlgh numbers of alrway
eoslnophlls and lymphocyLes
1hese alrway cells decrease slgnlcanLly aer
LreaLmenL wlLh lnhaled sLerolds
AuempLs Lo ldenufy blomarkers ln perlpheral blood
have been unsuccessful
Soluble lL-28, lL-4, lc epsllon 8ll
Serum eoslnophlllc cauonlc proLeln
Causes of Los|noph|||c 8ronch|ns
non-compllance
Cngolng allergen exposure
lnadequaLe sLerold dose
arasluc lnfecuon
Chronlc rhlnoslnuslus
vascullus
Chronlc eoslnophlllc pneumonla
Pypereoslnophlllc syndrome
Jayaram L, et al. Eur Respir J 2006;27:483-94.
Neutroph|||c Asthma
May have concomlLanL eoslnophlls
Cen seen ln severe asLhma
Cause unclear:
currenL/prevlous Lobacco smoke
occupauonal/lrrlLanL exposure
obeslLy
vlral lnfecuons
LreaLmenL wlLh hlgh dose sLerolds
decreases neuLrophll apopLosls
Anu-neuLrophlllc Lheraples have noL
been sysLemaucally sLudled
? 8ole for anubloucs
Anu lL-8
1lssue lnhlblLors of MM 9 (1lMs)
1nl alpha lnhlblLors
Causes of Neutroph|||c 8ronch|ns
vlral lnfecuons
non-bacLerlal lnfecuons
8acLerlal lnfecuons
8ronchlecLasls
lmmune declencles
Cysuc llbrosls
Clgareue smoklng
olluLanLs
Cccupauonal exposure
lnammaLory bowel dlsease
Chronlc asplrauon
Pallan S,et al. CHEST 2008;134:628-30.
Ind|canons for Sputum Ana|ys|s |n Asthma
AsLhma noL showlng adequaLe response Lo usual
Lherapy
Lxacerbauons of asLhma Lo deLermlne approprlaLe
Lherapy
ldenucauon of eoslnophlllc or neuLrophlllc
bronchlus as parL of occupauonal asLhma evaluauon
Can Exhaled NO Guide Asthma Therapy?
0
100
200
300
400
500
600
700
FENO
Control
F
l
u
t
i
c
a
s
o
n
e

d
o
s
e

(
u
g
/
d
a
y
)

p=0.36 p=0.003 p=0.003
Study Entry End Phase 1 End Phase 2
(optimal dose) (final visit)
Smith AD et al. NEJM 2005;352:2163-73.
No Difference:
-exacerbations
-sputum eos
-FEV1
-prednisone use
Exhaled volatile organic
compounds may be easier
Ibrahim B, et al. Thorax 2011;66:804-9.
henotypes Us|ng C|uster Ana|ys|s
Moore WC, et al. AJRCCM 2010;181:315-23.
-Early onset
-Atopic
-Normal PFTs
-<2 controllers
-Minimal HCU
-Early onset
-Atopic
-Normal PFTs
-More meds
-More HCU
-Late onset
-Non-atopic
-Moderate PFTs
-Mostly obese F
-Frequent OCS
- ~70% cluster 4 fulfill ATS severe asthma
- ~80% cluster 5 fulfill ATS severe asthma
- Equal gender - 63% women
- 72% child onset - 69% late onset
- 83% atopic - 66% atopic
- PFT severe/reversible Very severe, fixed
revennon of Asthma Lmergenc|es
some pauenLs have llfe LhreaLenlng auacks desplLe
good care
mosL severe reecL lnadequaLe
early recognluon
assessmenL and
managemenL of deLerloraung asLhma
emergencles are largely prevenLable by careful
monlLorlng and approprlaLe long- Lerm LreaLmenL of
asLhma
In|na| 1herapy
Cxygen
28-33 usually all LhaL ls needed
hlgh concenLrauons are safe
lnhaled bronchodllaLors
beLa-agonlsLs versus anuchollnerglcs
Mul wlLh spacer vs nebullzer
lnLermluenL vs conunuous
lnhaled vs oral vs lv
SysLemlc corucosLerolds
oral vs parenLeral
Cther 1herap|es
MeLhylxanLhlnes
only adds Lo LoxlclLy
don'L conslder ln rsL 4-6 hours
LeukoLrlene recepLor anLagonlsLs
may lmprove bronchodllaLor response (lv)
noL currenLly lndlcaLed for L8 LreaLmenL
mlghL have role ln prophylaxls vs vlral lnduced
Pellox
Magneslum sulfaLe
8lA
Magnes|um Lect on I1
8y In|na| Sever|ty of I||ness
0
5
10
15
20
25
Placebo
Magnesium
p<0.03
<20% 20-24.9% 25-30%
% Predicted FEV1 on ER Arrival

A
b
s
o
l
u
t
e

C
h
a
n
g
e

i
n

F
E
V
1


%

P
r
e
d
i
c
t
e
d

A
f
t
e
r

I
n
f
u
s
i
o
n

Silverman RA et al. CHEST 2002;122:489-97.
n=240
MgSO4 2 gms iv

Adm|ss|on or D|scharge
Cbserve for aL leasL 30 mlnuLe aer lasL
bronchodllaLor LreaLmenL
Admlsslon declslons should be made by Lhe 3-6 hour
mark ln L8
reLreaLmenL lLv1 or Ll8 <23 predlcLed usually
requlre admlsslon
lLv1 <1.0 llLre or Ll8 < 100 L/mln
Adm|ss|on or D|scharge
ulscharge lf:
lLv1 or Ll8 >30 predlcLed or known besL
> 60 denlLe candldaLes for dlscharge
40-60 depends on rlsk for relapse
<40 usually requlre admlsslon
lmprovemenL llkely Lo be susLalned
auenL wlll comply wlLh lnsLrucuons
lollow-up arrangemenLs are sausfacLory
D|scharge Instrucnons
MalnLaln oral corucosLerold 8x 7-14 days
Conunue/sLarL regular lCS Lherapy
Cpumlze bronchodllaLor Lherapy
8evlew slgns of worsenlng conLrol
Arrange for follow up educauon
envlronmenLal assessmenL and conLrol
role for varlous medlcauons
wrluen acuon plan
Controlled Uncontrolled
Confirm Diagnosis
Asthma Management Continuum
Children (6 years and over) and Adults
Fast-acting Bronchodilator on Demand
Environmental Control, Education and Written Action Plan
12 yrs: Add LTRA

6-11 yrs: Increase ICS
12 yrs: Add LABA*
Anti-IgE

Prednisone
6-11 yrs: Add LABA or LTRA
Inhaled Corticosteroid (ICS)*
*Second-Line: Leukotriene Receptor Antagonist (LTRA)
Low Dose Medium Dose High Dose
12 yrs: 250 mcg/day

251 500 mcg/day

>500 mcg/day


6-11 yrs: 200 mcg/day

201 400 mcg/day

>400 mcg/day


Regularly Reassess
Control
Spirometry or PEF
Inhaler technique
Adherence
Triggers
Co-morbidities
Sputum eosinophils

HFA Beclomethasone or equivalent; *Second-line: LTRA;

Approved for 12 years and over

Lougheed MD, et al. Canadian Thoracic Society 2012 Guideline update:. Can Respir J 2012;19:127-64.: