ACC

8oard kev|ew 2011

CCD art I
S|dney S. 8raman MD ICC
Mount S|na| Schoo| of Med|c|ne
New ork, N
D|sc|osures
ConsulLanL Sunovlon, 8l, loresL
non-promouonal Speaker CSk, CenenLech
Cb[ecnves
1. 1o revlew Lhe denluon of CCu LhaL descrlbes Lhls dlsease as an alrway and
sysLemlc lnammaLory condluon.
2. 1o explore Lhe lmpacL of CCu lncludlng morbldlLy and morLallLy.
3. 1o revlew Lhe rlsk facLors for CCu.
4. 1o explore Lhe naLural hlsLory of CCu
3. 1o explore Lhe currenL undersLandlng of Lhe paLhophyslology of CCu: Lhe
paLhologlc consequences of alrway lnammauon and parenchymal lung
desLrucuon.
6. 1o explore Lhe sysLemlc consequences of Lhe dlsease and Lhe co-morbldlues
assoclaLed wlLh CCu.
7. 1o revlew Lhe currenL sLaLe of pharmacologlc and non-pharmacologlc Lherapy for
CCu lncludlng prevenuve measures such as smoklng cessauon.
GOLD 2007
GCLD Dehn|non of CCD
CCu ls a prevenLable and LreaLable dlsease wlLh some
slgnlcanL exLrapulmonary eecLs LhaL may conLrlbuLe Lo Lhe
severlLy ln lndlvldual pauenLs.
lLs pulmonary componenL ls characLerlzed by alrow
llmlLauon LhaL ls noL fully reverslble.
1he alrow llmlLauon ls usually progresslve and assoclaLed
wlLh an abnormal lnammaLory response of Lhe lung Lo
noxlous parucles or gases.
Cigarette smoke
Occupational dust and
chemicals
Environmental tobacco
smoke (ETS)
Indoor and outdoor
air pollution
GOLD 2007
Cumu|anve Lxposure to Nox|ous arnc|es
|s the key k|sk Iactor for CCD
SLage l: Mlld lLv
1
/lvC < 0.70
lLv
1
> 80 predlcLed

SLage ll: ModeraLe lLv
1
/lvC < 0.70
30 < lLv
1
< 80 predlcLed

SLage lll: Severe lLv
1
/lvC < 0.70
30 < lLv
1
< 30 predlcLed

SLage lv: very Severe lLv
1
/lvC < 0.70
lLv
1
< 30 predlcLed !"
lLv
1
< 30 predlcLed $%&' chronlc resplraLory
fallure
www.goldcopd.com
GCLD C|ass|hcanon of CCD Stag|ng by
Sp|rometry
Adapted with permission from GOLD 2011 Guidelines. Global Strategy for the Diagnosis,
Management, and Prevention of Chronic Obstructive Lung Disease 2011. Global Initiative for
Chronic Obstructive Lung Disease. www.goldcopd.org. Accessed March 30, 2012.
GCLD 2011 Gu|de||nes:
Comb|ned Assessment of CCD
C D
A B
4
3
2
1
#2
1
0
mMRC 0-1
CAT <10
Symptoms
mMRC or CAT score
R
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k

E
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h
i
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r
y

mMRC #2
CAT # 10
R
i
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G
O
L
D

c
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s
i

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o
f

a
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o
w

l
i
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Patient Group A
Low risk
Less symptoms

GOLD grade 1 or 2
Exacerbations/yr 0-1
Symptoms mMRC 0-1 or CAT <10
Patient Group B
Low risk
More symptoms
GOLD grade 1 or 2
Exacerbations/yr 0-1
Symptoms mMRC #2 or CAT #10
Patient Group C
High risk
Less symptoms
GOLD grade 3 or 4
Exacerbations/yr #2
Symptoms mMRC 0-1 or CAT <10
Patient Group D
High risk
More symptoms

GOLD grade 3 or 4
Exacerbations/yr #2
Symptoms mMRC #2 or CAT #10
When assessing risk, choose the highest risk according to GOLD
spirometry grade or exacerbation history
mMRC: Modied Medical Research Council dyspnea scale
CAT: COPD Assessment Test

SeverlLy

osLbronchodllaLor
lLv1/lvC

lLv1 pred.
AL rlsk
(Smokers, +famlly hx, eLc)
>0.7 >80
Mlld CCu <0.7 >80
ModeraLe CCu <0.7 30-80
Severe CCu <0.7 30-30
very severe CCu <0.7 <30
Celli et al Eur Respir J 2004; 23:932-946
A1S]LkS C|ass|hcanon of CCD
Stag|ng by Sp|rometry
uesnon 1
33 year old man presenLed wlLh a 3 year hlsLory of
shorLness of breaLh on exeruon, worse followlng a vlral
resplraLory lnfecuon. Pe had asLhma as a chlld and was a
smoker (1u) for 23 years. ulmonary funcuon Lesung
showed a moderaLely severe degree of obsLrucuon. Whlch
of Lhe followlng LesLs have been shown Lo dlsungulsh
asLhma from CCu?
uesnon 1
Wh|ch of the fo||ow|ng tests best d|snngu|sh asthma
from CCD?
Choose the best answer

a) 8ronchlal lnhalauon challenge wlLh meLhachollne
b) An lLv1 response Lo a shorL acung beLa agonlsL
of > 12 lmprovemenL (and > 200 cc lncrease)
c) MeasuremenLs of lung volumes (1LC, l8C, 8v)
d SpuLum eoslnophll counL
D|snngu|sh|ng Asthma and CCD
8oLh may lead Lo xed alrow obsLrucuon buL mosL show
reverslblllLy Lo shorL-acung bronchodllaLors
ulerences ln lung funcuon LesLs (dluslng capaclLy, resldual
volume,
a
C
2
) sLausucally slgnlcanL buL Lhere ls large overlap
CCu has hlgher emphysema score on P8C1
Lxhaled nC hlgher ln asLhmaucs buL Lhere ls overlap
AsLhmaucs have slgnlcanLly more eoslnophlls ln Lhe perlpheral
blood, spuLum and 8AL, CCu, lncreased neuLrophlls spuLum
and 8AL
CCD and AS1nMA: D|erent D|seases
.
COPD
Affects elderly,
especially smokers
Slowly progressive
Inflammatory cells

Partially reversible
? 10%
ASTHMA
Affects all ages,
especially childhood
Episodic course
Inflammatory cells
Eosinophilc bronchitis
Neutrophils in severe disease
Overlap syndrome
May be fully reversible

Neutrophilic bronchitis


Eosinophils during
exacerbation

Airway remodeling and
Lung destruction


Airway remodelling
no destruction
Some patients with asthma cannot be distinguished from COPD with
the current diagnostic tests. The management of these patients should
be similar to that of asthma. ATS Guidelines 2004
D|snngu|sh|ng Asthma and CCD*
Fabbri et al AJRCCM 2003;167:418-24
Sputum Eosinophils >4.6% Exhaled NO is
distinguish the 2 diseases not able to distinguish
*FEV1= 56% predicted
Fabbri et al AJRCCM 2003;167:418-24

atho|og|c Changes: Asthma vs CCD
Asthma shows |mmunosta|n|ng for eos|noph||s (8)
and th|ckened basement membrane (D)

*

Sputum Neutroph||s S|gn|hcant|y
Increased Dur|ng a CCD Lxacerbanon
Fujimoto K, et al. Eur Respir J. 2005;25:640-646.
Results of nonsmokers from a stable phase and during an exacerbation in patients who developed
an exacerbation during the study.
*P<0.01 vs nonsmokers.

P<0.05 vs stable phase.

M
e
a
n

N
e
u
t
r
o
p
h
i
l
s

x

1
0
5
/
g

0
50
100
150
200
250
300
350
Stable Phase During
Exacerbation
Nonsmokers
(n=11)
(n=30)
*
Sputum Los|noph||s S|gn|hcant|y
Increased Dur|ng a CCD Lxacerbanon
Fujimoto K, et al. Eur Respir J. 2005;25:640-646.
Results of nonsmokers from a stable phase and during an exacerbation in patients who developed an
exacerbation during the study.
*P<0.01 vs nonsmokers.

P<0.05 vs stable phase.

M
e
a
n

E
o
s
i
n
o
p
h
i
l
s

x

1
0
5
/
g

0
2
4
6
8
10
12
14
16
18
20
Stable Phase During
Exacerbation
*
Nonsmokers
(n=11)
(n=30)
*

Near|y 2]3 of panents w|th severe CCD (mean ILV
1

39.3 pred) respond to bronchod||ators* (1S or 12 &
200 m| |ncrease |n ILV
1
)
Tashkin DP, et al. Eur Respir J.2008;31:742-750.
UPLIFT Trial
(n=5756)
P
e
r
c
e
n
t

o
f

P
a
t
i
e
n
t
s

65.5%
* Ipratropium and albuterol
Ma[or|ty of CCD panents show kevers|b|||ty
(kesponse to A|butero| or Ipratrop|um)
Albuterol
27%
Albuterol and
Ipratropium
35%
Not reversible
to either drug
27%
Ipratropium
11%
Mahler D 1999 Chest;116:1137
8ronch|a| nyperrespons|veness (8nk) and
CCD
63 of men and 87 of women show 8P8 ( >= 20 fall ln lLv
1

wlLh<= 23 mg/mL meLhachollne, lndlcaung alrway
hyperresponslveness (AP8)
1
8P8 has negauve prognosls: assoclaLed wlLh acceleraLed decllne
ln lLv
1
over ume
8P8 assoclaLed wlLh lncreased morLallLy
Smoklng cessauon has posluve eecL on 8P8 & lmproves lLv
1
greaLer ln Lhose wlLh 8P8
Tashkin D et al Am Rev Respir Dis 1992; 145(2 Pt 1):301-10
Wise RA et al Chest 2003;124:449-58

High resolution computed tomography (HRCT):
A reliable tool for demonstrating the pathology of
emphysema
ulmonary emphysema ls classled lnLo Lhree Lypes relaLed
Lo Lhe lobular anaLomy:
cenLrllobular emphysema: enlargemenL of dllaLed alrspaces cause
evenly dlsLrlbuLed areas of low auenuauon wlLh lll-dened
borders.
anlobular emphysema: panlobular low auenuauon or lll-dened
dluse low auenuauon of Lhe lung.
arasepLal emphysema: characLerlzed by subpleural well-dened
cysuc spaces.
Takahashi et al Int J Chron Obstruct Pulmon Dis. 2008;3:193-208
Anatomy of the
Secondary u|monary Lobu|e
BR, bronchus; PA, pulmonary artery; PV, pulmonary vein; ILS,
interlobular septum Short arrow=terminal bronchioles
Centr||obu|ar Lmphysema
nkC1 demonstrates Low Auenuanon |n the Centr|ac|nar Area
Inflated fixed lung
Moderate|y Advanced Centr||obu|ar
Lmphysema
an|obu|ar Lmphysema
Un|form d||atanon of the a|rspaces from
resp|ratory bonch|o|es to a|veo||
arasepta| emphysema: character|zed by
subp|eura| we||-dehned cysnc spaces.
Accelerated form of pulmonary emphysema in a stable HIV-seropositive outpatient
8u||ous Lung D|sease: a r|sk factor for
8ronchogen|c Carc|noma
Lung Cancer and CCD
8ullous lung dlsease has 32 umes hlgher rlsk of developlng
lung cancer
CCu a sLrong assoclauon beLween CCu and lung cancer,
buL Lhls was largely explalned by Lhe eecL of smoklng
A sLrong relauonshlp beLween boLh CCu and pneumonla
and lung cancer ln Lhe 6 monLhs lmmedlaLely before lung
cancer dlagnosls- geL a chesL xray wlLh new dlagnosls

Powell et al J lournal of Thoracic Oncology Jan 2013
uesnon 2
A 34 year old pauenL who smokes 1-2 packs of clgareues a
day ls ndlng lL dlmculL Lo qulL. Pls pulmonary funcuon
LesLs show CCLu SLage l dlsease. Pe ls cllnlcally well and
has a negauve pasL medlcal hlsLory. Whlch sLaLemenL ls
mosL correcL abouL Lhls man wlLh a normal lLv
1
?
uesnon 2
Choose the most correct statement
a) 8AL would show a normal values for alveolar macrophages
and neuLrophlls aL Lhls early sLage of dlsease.
b) lf he conunues Lo smoke he wlll llkely (>90 chance)
progress from CCLu SLage l Lo lv CCu
c) 8efore he developed CCLu SLage l CCu lncreased numbers
of lnammaLory cells would be absenL
d) Small alrways show hyperplasla of gobleL cells and mucous
gland hyperplasla
Mucus G|ands Are Ln|arged |n CCD
Hogg. Int J Tuberc Lung Dis. 2008;12:467-479.
A muluvarlaLe analysls has shown LhaL Lhlckenlng of Lhe walls of Lhe small conducung
alrways and occluslon of Lhelr lumen by lnammaLory exudaLes conLalnlng mucus
explalns more of Lhe varlance ln Lhe assoclauon beLween lLv1 decllne and hlsLology
ln CCu Lhan Lhe lnlLrauon of Lhe ussue by any lnammaLory cell Lype.
Inammatory Ce||s and CCD
SLudles show LhaL asympLomauc smokers, sympLomauc
smokers (CCLu sLage 0), and smoklng pauenLs wlLh CCu
have a large overlap ln lnammauon as assessed ln spuLum
and alrway wall blopsles
Willemse et al Respiratory Research 2005, 6:38
Numbers of Inammatory Ce||s and Med|ators
Increase as D|sease rogresses
120
100
80
60
40
20
0
PMNs Macrophages Eosinophils
Acute Inflammatory Cells
67
55
84
100
54
66
73
92
25
33
29
32
A
i
r
w
a
y
s

w
i
t
h

M
e
a
s
u
r
a
b
l
e

C
e
l
l
s

(
%
)

120
100
80
60
40
20
0
CD4 cells CD8 cells B Cells
Inflammatory Cells
GOLD Stage 0
GOLD Stages 2
and 3
GOLD Stage 1
GOLD Stage 4
63
87
77
94
85
80
88
98
7
8
45
37
A
i
r
w
a
y
s

w
i
t
h

M
e
a
s
u
r
a
b
l
e

C
e
l
l
s

(
%
)

Hogg JC et al. New Engl J Med 2004; 350: 26452653.
GOLD Stage 0
GOLD Stages 2
and 3
GOLD Stage 1
GOLD Stage 4
PMN = Polymorphonuclear Cells
Vo|ume of a|rway wa|| nssue shows a strong assoc|anon
w|th d|sease progress|on (! < 0.001).

0 20 40 60 80 100 120
0.25
0.20
0.15
0.10
0.05
0
GOLD
Stage 4
FEV
1

V
:
S
A

(
m
m
)

GOLD
Stage 3
GOLD
Stage 2
GOLD
Stages 0 and 1
Hogg et al. New Engl J Med. 2004;350:2645-2653.
.

CCD Inammanon and atho|ogy
Hogg JC. Lancet 2004; 364: 709721.
Normal
Bronchiole
Bronchiole
with Mucus
Bronchiole
with
Inflammatory
Exudate and
Mucus
End-Stage
Mechan|sms Under|y|ng
A|row L|m|tanon |n CCD
Inflammation
Small Airway Disease Parenchymal Destruction
Airflow Limitation
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed February 12, 2002
Normal Lung Parenchyma
Chronic Obstructive
Bronchiolitis
Emphysema Barnes. N Engl J Med.
2000;343:269-280.
Vlahovic. Am J Respir Crit Care
Med. 1999;160:2086-2092.
.

n|stopatho|og|ca| Ieatures
of CCD
Inammanon Leads to
Sma|| A|rway Narrow|ng
AcuLe and chronlc lnammauon conLrlbuLes Lo CCu-
relaLed small alrway narrowlng
Alrway narrowlng leads Lo alrway obsLrucuon
narrowlng resulLs from several facLors
Collagen deposluon and lncreased lymphold folllcles ln ouLer
alrway wall
Mucosal Lhlckenlng narrows alrway lumen
lnammaLory exudaLe ln alrway lumen
Barnes PJ et al Eur Respir J 2003
A|rway kes|stance |n Sma|| A|rways
1he conLrlbuuon of Lhe
small alrways Lo alrow
reslsLance ls small because
of Lhe large cross secuonal
area ln Lhls zone
Larly small alrway changes
of CCu may noL be
measured by l1s (lLv
1
)
M||d Low Lung Iuncnon Abnorma||nes |n
Smokers Chen Do Not rogress to CCD
Anthonisen, AJRCCM 2002 166;675-679
One-third of LHS
smokers never
developed impaired
lung function after 11
years, despite airway
obstruction at
baseline.
FEV1 % predicted at year 11
(n=1054)
*
*
*
38% show
FEV1<60%
At 11 yrs

18% show
FEV1<50%
At 11 yrs

1he Inammatory Ce||s of CCD
()&*"!$+,%'
oLenL chemoklnes (lL-8) and L184 auracL neuLrophlls
lncreased numbers ln spuLum and 8AL uld, noL alrway walls
neuLrophll numbers correlaLe wlLh CCu severlLy
SecreLe proLelnases: neuLrophll elasLase, caLhepsln and proLelnase-3-A causauve
llnk Lo mucus hypersecreuon

- -.//"!$+.0)'
- AcuvaLed by clgareue smoke
- lncreased numbers found ln spuLum, 8AL and lungs
- 8elease lnammaLory medlaLors: 1nl!, L184, lL-8, 8CS and proLelnases

Inammanon |n CCD
1he 1 Lymphocyte
CCu assoclaLed wlLh an lncrease ln 1 lymphocyLes ln Lhe
alrway wall
1here ls a shl ln Lhe balance of Cu4
+
/Cu8
+
1 cell rauo ln
favor of Cu8
+
Cu8
+
lymphocyLes are found ln Lhe large and small alrway
walls, Lhe lung parenchyma and advenuual layer of Lhe
pulmonary arLerles
SlgnlcanL correlauon beLween cyLoLoxlc Cu8
+
lymphocyLes
and Lhe degree of alrow obsLrucuon
Increased CD8+ Ce|| Numbers |n the
Submucosa of Large and Sma|| A|rways,
Vesse|s and A|veo|ar Wa|| of Smokers Who
Deve|op CCD
Saetta et al. Am J Respir Crit Care Med. 1999;160:711-717.
L
I
E
Jeffery PK. Chest 2000; 117: 251S260S.
Courtesy of Dr Marina Saetta
CD8
+
Lymphocyte Count
Increases as CCD rogresses
Smoker with
Mild COPD
Smoker with
Severe COPD
(Immunostaining with anti-CD45 monoclonal antibody. Positive cells in red x400)
Turato G et al. Am J Respir Crit Care Med 2002;166:105-110.
Saetta et al. Am J Respir Crit Care Med. 1998;157:822-826.
P = 0.01
rho = -0.63
0
200
400
600
1000
0 50 60 70 80 90 110
FEV
1
(% Predicted)
C
D
8
+

(
c
e
l
l
s
/
m
m
2
)

1he Greater the CD8+ Inh|tranon,
the Greater the A|rway Cbstrucnon
100
800
uesnon 3
A 43 year old pauenL who smokes 1-2 packs of clgareues a
day ls ndlng lL dlmculL Lo qulL. Pls pulmonary funcuon
LesLs show CCLu SLage ll dlsease. Pe ls cllnlcally well and
has a negauve pasL medlcal hlsLory. Whlch sLaLemenL ls
mosL correcL abouL pauenLs llke Lhls wlLh CCLu SLage ll
CCu
uesnon 3
Wh|ch statement |s most correct?
a. Smoklng cessauon wlll reduce Lhe raLe of CCu decllne ln lung
funcuon
b. 1he sLrucLural changes lnluaLed by smoklng wlll evenLually
resolve aer smoklng cessauon has been achleved.
c. Aer one year of smoklng cessauon Lhe alrway lnammaLory
cells wlll noL be seen on 8AL
d. Cxldauve sLress from of reacuve oxygen specles (8CS) ends
soon aer smoklng cessauon
0
20
40
60
80
100
20 30 40 50 60 70 80 90
FEV
1

(%)
Age (years)
Death
Disability
Quit Age 45
Age 65
Fletcher C, Peto R. Br Med J. 1977;1:1645-1648.
CCD k|sk and Smok|ng Cessanon
Never smoked or
not susceptible
Smoked and
susceptible
rogress|ve A|rway Cbstrucnon:
Causes
1) ro-lnammaLory medlaLors
2) roLeolyuc dlgesuon of lung ussue.
3) Cxldauve sLress
keacnve Cxygen Spec|es
kCS
8CS are generaLed from chemlcal reacuons wlLhln Lhe clgareue smoke
or from neuLrophlls and macrophages aer sumulauon by clgareue
smoke.
8CS poLenuaLe Lhe lnammaLory response, dlrecLly by lncreaslng
mucus secreuon, and lndlrecLly vla muluple medlaLors, parucularly 1nl-
!.
1oxlc 8CS are capable of dlrecLly causlng ussue desLrucuon: plasma
leakage, bronchoconsLrlcuon) or Lhey can sumulaLe oLher lnammaLory
paLhways (e.g. leadlng Lo a reducuon ln anu-proLeases).
kCS
CorucosLerolds recrulL PuAC2 Lo acuvely Lranscrlblng genes,
whlch reverses lnammaLory process by swlLchlng o
lnammaLory gene Lranscrlpuon.
ln pauenLs wlLh CCu, PuAC2 funcuon ls lmpalred by
clgareue smoklng and oxldauve sLress, leadlng Lo a
pronounced reducuon ln responslveness Lo corucosLerolds.
Kirkham and Barnes Chest 2013;144:26-2736
" Anti-Proteases
!
1
-anti-trypsin
and secretory
leukoprotease
inhibitor
" HDAC2
Corticosteroid
Resistance
IL-8 TNF-!
Neutrophil Recruitment
Activation of Nuclear Factor #B
CCD: Cx|danve Stress |s Centra| to the Destrucnon
of u|monary 1|ssue
Bronchoconstriction
Cigarette Smoke
Inflammatory cells (neutrophils,
macrophages)
Isoprostanes
ROS
ROS = Reactive Oxygen Species
.
$ Mucus Secretion
Plasma Leak
.
Reproduced from The Lancet, Vol 363, Barnes et al.

uesnon 4
A 33 year old man, a recenL lmmlgranL from a small vlllage ln lndla, ls
referred because of dyspnea and alrow obsLrucuon. 8efore comlng
Lo Lhe uS he was exposed Lo cadmlum fumes as he worked ln a
facLory LhaL makes auLo bauerles. Pls lLv1 ls 1.3 L (40 pred.) LhaL ls
noL reverslble aer an lnhaled shorL-acung 8u. Pe never smoked buL
has a hlsLory of poorly conLrolled aLoplc asLhma as a chlld. 1here have
been no recenL asLhma auacks buL he has had many auacks of acuLe
bronchlus ln recenL wlnLers. Whlch of Lhe followlng sLaLemenLs ls
mosL correcL regardlng hls alrow obsLrucuon?
uesnon 4
Wh|ch statement |s correct?
a) Alpha-1 anuLrypsln declency ls Lhe mosL llkely cause of hls poor
lung funcuon
b) Lxposure Lo parenLal smoklng and blomass fuel as a chlld are
assoclaLed wlLh recurrenL bronchlal lnfecuons buL noL CCu ln
adulLhood
c) 1he lack of any bronchodllaLor reverslblllLy would rule ouL
asLhma as a cause
d) Pls work as a bauery facLory worker (cadmlum fumes) may have
caused CCu ln Lhls pauenL
IS ALnA-1 AN1I1kSIN DLIICILNC
1nL CAUSL CI nIS AIkILCW C8S1kUC1ICN?
athogenes|s of CCD
Noxious Particles and Gases
Lung Inflammation
COPD Pathology
Antioxidants Antiproteinases
Host Factors
Oxidative Stress
Proteinases
NIH/NHLBI. Global Initiative for Chronic Obstructive Lung Disease. NHLBI/WHO Workshop Report 2001.
Available at: http://www.goldcopd.com/workshop.html. Accessed February 12, 2002
rote|nases |n CCD
roLelnases lnvolved ln alveolar wall desLrucuon
Smokers have hlgh levels of neuLrophll elasLase (nL) ln 8AL
uld, & hlgher when emphysema presenL
nL degrades elasun ln elasuc ussue
MaLrlx meLalloproLelnases (MMs) can degrade all
elemenLs of exLracellular maLrlx
Collagen breakdown and synLhesls ls also a feaLure of
emphysema
rote|nases |n CCD
An lmbalance beLween neuLrophll elasLase ln Lhe lung,
whlch desLroys elasun, and Lhe elasLase lnhlblLor, alpha-1
anuLrypsln (AA1), whlch proLecLs agalnsL proLeolyuc
degradauon of elasun, causes early CCu ln smokers
A|pha-1 Anntryps|n Dehc|ency
Ma[or manlfesLauon ls pan-aclnar emphysema- posslbly
asLhma, bronchlecLasls
1-3 of pauenLs wlLh CCu
roLecuve Lhreshold level= 11 mcmol/L
CCu occurs laLer ln non-smokers ( 3
Lh
decade and beyond):
oLher rlsk facLors are pneumonla, chesL colds, wheezlng
A|pha-1 Anntryps|n Dehc|ency
C||n|ca| Ieatures
Larly-onseL emphysema< 43 years
Lower lobe bullae/emphysema
unexplalned llver dlsease
necrouzlng pannlcullus
C-AnCA posluve vascullus
lamlly hlsLory of CCu, bronchlecLasls, pannlcullus
unremlmng asLhma wlLh alrow obsLrucuon
no obvlous rlsk facLor
CCD and 8|omass Iue|
Worldwlde, abouL 30 of all households and 90 of rural
households use blomass fuel (wood, charcoal, oLher
vegeLable mauer, and anlmal dung) and coal as Lhelr maln
source of domesuc energy.
AbouL 30 of CCu deaLhs ln developlng counLrles are from
blomass smoke, 73 are of women.
Lxposure Lo blomass smoke ls slgnlcanLly assoclaLed wlLh
acuLe resplraLory-LracL lnfecuon (364, 21-64) and CCu
(odds rauo 23, 93 Cl 13-33)
urled anlmal dung and scavenged Lwlgs and grass, whlch
are cheap are lnemclenL and mosL polluung,
Salvi et al Lancet 2009; 374: 73343
k|sk Iactors for CCD |n Ch||dhood
lmpalred growLh of lung funcuon durlng chlldhood and
adolescence, can be caused by recurrenL lnfecuons and
parenLal smoklng and Lhls may lead Lo lower lung funcuon
ln early adulLhood
Wang et al Am J Respir Crit Care Med. 1994;149:1420-5.
CCD Caused by
Lnv|ronmenta| 1obacco Smoke (L1S)
LnvlronmenLal exposure has been llnked Lo causlng asLhma
ln chlldren and adulLs
Plgher cumulauve llfeume home and work exposure ls also
assoclaLed wlLh a greaLer rlsk of developlng CCu
L1S exposure may be an lmporLanL cause of CCu, Lhe
hlgher Lhe exposure Lhe hlgher Lhe rlsk
Eisner et al Environ Health. 2005;4:7
Cccupanona| CCD
1S of CCD aur|butab|e to occupanona| exposure
uusL exposure hlgher rlsk Lhan gas/fumes
nPAnLS lll survey showed LhaL Lhe proporuon of pauenLs
wlLh CCu aurlbuLable Lo occupauon was abouL 19
overall and 31 ln never-smokers.
Cadmlum lumes cause Lmphysema
Blanc PD et L Int J Tuberc Lung Dis 2007; 11: 25157.
Cccupanona| CCD
Crop farmlng: graln dusL, organlc dusL, lnorganlc dusL
Anlmal farmlng: organlc dusL, ammonla, hydrogen sulphlde
uusL exposures: coal mlnlng, hard-rock mlnlng, Lunnelllng,
concreLe manufacLurlng, consLrucuon, brlck manufacLurlng,
gold mlnlng, lron and sLeel foundlng
Chemlcal exposures: plasuc, Lexule, rubber lndusLrles,
leaLher manufacLurlng, manufacLurlng of food producLs
olluLanL exposure: LransporLauon and Lrucklng, auLomouve
repalr
A|rway kemode||ng
I|xed A|rway Cbstrucnon of Asthma
8oLh chlldren and adulLs wlLh no sympLoms may show xed
alrow obsLrucuon
auenLs wlLh severe asLhma are Lhose more llkely Lo have
lrreverslble obsLrucuon
Some pauenLs wlLh asLhma have a sLeeper raLe of decllne/
yr of lLv
1
(3-23ml>normal)
AsLhma beglnnlng >age 30 has sLeeper decllne Lhan younger
asLhmaucs
Cellular Proliferation
Extracellular Matrix
Increase

Airway
Remodeling
SmooLh muscle mass lncreases
Mucous glands hyperLrophy
8lood vessels engorge
lnammaLory cells perslsL
Collagen (Lype lll & v) ls deposlLed ln
8M (lamlna reucularls) and ln LC
space
Abnormal alveolar auachmenLs wlLh
decreased elasuc ber conLenL Loss
of elasuc recoll, buL no desLrucuon
A|rway kemode||ng
I|xed A|rway Cbstrucnon of Asthma
1nANk CU ICk CUk A11LN1ICN!