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Andrew Bush MD FRCP FRCPCH FERS
Imperial College & Royal Brompton Hospital
Risk factors and early origins
of COPD
COI statement
• None relevant to this presentation
• In addition to my main employment, I am EIC
of Thorax, during which tenure I have made
many enemies, and from which I derive no
personal benefit
Aims of the Presentation
• My talk focuses on premature airflow obstruction, a
description not a disease – I don’t understand ‘COPD’
• To demonstrate the crucial importance of childhood
events in the development of premature airflow
obstruction
• To remind us that there is more to lung development than
just the airway
• To show that childhood life events are not evanescent
phenomena but have profound long term significance
The early roots of ‘COPD’
• Some fundamental preliminary observations
• ‘COPD’ vs. premature airflow obstruction
• Safe in the womb?
• Birth right?
• Think beyond the airway
• Summary and conclusions
Four fundamental observations
• GLI data www.lungfunction.org
• 97,759 records,
healthy non-
smokers from 72
centres in 33
countries age 2.5-
95 years
• Constructed
predictive
equations for
spirometry
Males
Eur Respir J 2012; 40: 1324-43
Barkerology: If you can’t measure it well, measure it often!
MALES FEMALES
0
1
2
>3
Age (yrs)
COPD &
Childhood
ECFS study • 13,359 aet 20-45
Risk factors • Maternal asthma
• Paternal asthma
• Childhood asthma
• Maternal smoking
• Childhood resp.
infections
Early childhood disadvantage:
Lower lung function
No catch-up
Faster rate of decline
More COPD
Thorax 2010; 65: 14-20
Effect of Childhood Disadvantage
=
Effect of Heavy Smoking
60
70
80
90
100
7 10 14 21 28 35 42
age at review (years)
FE
V1/F
VC
c
mwb
wb
a
sa
Lung function Changes over time
Nearly 50% SA now have COPD!
Stronger signal than smoking
The early roots of ‘COPD’
• Some fundamental preliminary observations
• ‘COPD’ vs. premature airflow obstruction
• Safe in the womb?
• Birth right?
• Think beyond the airway
• Summary and conclusions
FEV1/FVC ratio <70%
Disease Inflammation BHR PAL
BPD survivor No Yes Yes
Late asthma Variable Yes Yes
OB post AV No No Yes
Cystic fibrosis Neutrophilic Maybe Yes
‘COPD’ Variable Maybe Yes
PCD Neutrophilic Maybe Yes
Bronchiectasis Neutrophilic Maybe Yes
Do we REALLY lump these all together?
Normal or Diseased?
• Women aged 30,
FEV1/FVC ratio of
75% is wildly
abnormal
• Above age 50,
increasing numbers
of normal people will
have FEV1/FVC ratio
<70%
• Above age 70, >30%
of normal people will
have FEV1/FVC ratio
<70%
Is somebody weighing 50 kg
underweight whatever their age?
So, what does the FEV1/FVC
ratio actually mean? • Interpretation depends on developmental stage; exactly as
does height and weight
• FEV1/FVC ratio > 1.96 Z (SD) scores below the normal is not a
diagnosis, it merely describes airflow obstruction, which may
be the final common pathway of many diseases (cf raised
creatinine in kidney disease)
• I will be discussing FEV1/FVC ratio more than 1.96 Z scores
below the normal, not COPD, in the rest of this talk
• I believe COPD as a diagnostic term is as outmoded as
‘anaemia’ or ‘arthritis’ (and the same for ‘asthma’, incidentally)
The early roots of ‘COPD’
• Some fundamental preliminary observations
• ‘COPD’ vs. premature airflow obstruction
• Safe in the womb?
• Birth right?
• Think beyond the airway
• Summary and conclusions
Cigarettes: structure Antenatal collagen
deposition
MUC5AC expression
Alveolar tethering
points
RedJ 2002; 26: 31-4
RedJ 2011; 44: 222-9
BlueJ 2003; 163: 140-4
Cigarettes: more on structure • Increased ASM thickness BlueJ 2003; 163: 140-4
• Airway lengthening and reduced calibre
• AHR independent of allergen exposure RedJ 2012; 46: 695-72
READOUT IN THE BABY
• Airway obstruction and AHR at birth
• Long term signalling from both AHR and obstruction
COPSAC Data • 411 high-risk babies
• 403 (98%) RVRTC and
BHRmeth (TcPO2)
• Follow-up age 7 n=317 (77%)
, spirometry, questionnaire
• Neonatal airflow obstruction
predictive of asthma
• Obstruction age 7: 40%
antenatal, 60% postnatal
Neonatal BHR
• OR for later asthma 1.59
(1.11-2.28, p=0.001)
• Stronger predictor for later
asthma than neonatal lung
function
Am J Respir Crit Care Med 2012; 185: 1183-9
Cigarettes: Function Increased cord
blood MNC allergen
Response
CEA 2002; 32: 43-50
Reduced cytokine
& TLR function
Eur Respir J 2006;
28: 721-9
Abnormal cytokine
responses and
increased viral
Infections
BlueJ 2004; 170: 175-80
More on cigarettes! More likely to have asthma
More likely to smoke
Synergistic effects if
mother and child smoke
Thorax. 2013; 68: 1021-8
Daughter more
likely to smoke
Daughter more
likely to have asthma
Grandchildren more likely to have asthma
Antenatal
Postnatal
Chest 2005; 127: 1232-41
Magnus, Thorax, epub
The half was not told to me!
• Grandmaternal smoking
– Children more likely to be
LBW/preterm
– Children more likely to have
asthma
– Children more likely to smoke
– Grandchildren more likely to
have asthma
• Mother smoking
– Children more likely to be
LBW/preterm
– Children more likely to have
asthma
– Children more likely to smoke
– Lung function much worse if
child and mother smoke
Pollution!
• 624 children, spirometry age
4.5 years
• Developmental residential
exposure to benzene, NO2
• Effects for pregnancy, and
no other time point,
including recent and current
• Worse for allergic children,
low SES
Morales E, Thorax 2014; epub
The early roots of ‘COPD’
• Some fundamental preliminary observations
• ‘COPD’ vs. premature airflow obstruction
• Safe in the womb?
• Birth right?
• Think beyond the airway
• Summary and conclusions
Place of delivery, fecal flora &
asthma
WHAT THEY DID
• Fecal samples collected
@ 1 month (n=1167)
• Blood samples for sIgE
– Age 1 (n=921)
– Age 2 )n=82)
– Age 6-7 (n=384)
• Repeated questionnaires
birth-age 7
WHAT THEY FOUND
• C Diff isolation at one month associated with wheeze and eczema thru’ 6-7 years
• Atopic parents, home vaginal delivery – Reduced eczema (0.52,
0.35-0.77)
– Reduced asthma (0.47, 0.29-0.77)
JACI 2011; 128: 948-55
What about the
‘late pre-termer’?
• Does only very
preterm delivery
matter?
• ALSPAC: 25-32, 33-
34, 34-35, >36 weeks
gestation
• Spirometry at 8-9
and 14-17 years
Down As 25-32 35-36 & term same Spirometry age 8-9
Spirometry age 14-17 FEV1/FVC
FEF25-75
STILL down
Thorax 2012; 67: 54-61
What is the burden of “Asthma”?
• 44,173 women
delivering between
1989 and 2008
• N=2661 children had
asthma meds
reimbursed, 41512
controls
• Early term 108 extra
cases, biggest burden
• Post-term seemed to
be protective
mod
pre-
term
late pre-
term
early
term
Term late
term,
post-
term
N=
968
N=
2355
N=
7704
N=
22804
N=
10342
<32/40 33-
36/40
37-
38/40
39-
40/40
>41/40
3.9 (3.2-
4.8)
1.7 (1.4-
2.0)
1.2 (1.1-
1.4)
1.0 0.9
(0.8-1.0)
Window for intervention?
Combining atopy and wheeze
phenotypes • Manchester birth cohort
• 4 wheeze phenotypes
– None
– Transient
– Late onset
– Persistent
• 5 atopy phenotypes
– None
– Dust mite
– Non-dust mite
– Multiple early
– Multiple late
Pollution and
Lung Function • 64 healthy children
studied
• Carbon particles in
induced sputum
macrophages
• The more carbon in the
cells, the worse lung
the function of the child
NEJM 2006; 355: 21-30
Preterm Birth:
a new adult disease?
• Becoming MORE
common
• Effects cannot be
ameliorated by
surfactant, etc.
• An important future
‘COPD’ risk group!?
Airway Inflammation
& BPD
• N=17 asthmatics, normals,
BPD survivors
• Spirometry, & FeNO and
exhaled breath temperature
as measures of airway
inflammation
• BPD results
– Worse lung function
– Lower FeNO
– Exhaled breath temperature
• Conclusion: despite BHR, no
evidence of ongoing
inflammation in BPD Pediatr Pulmonol 2010; 45: 1240-5
They have AHR!
• BPD vs. non-BPD vs. term
• Acute BDR, diurnal variation,
AHR
Birthweight in Index Study Group SGA Subjects
200018001600140012001000800600
zM
EF
25
75
2
1
0
-1
-2
-3
-4
-5
Birth Weight in SGA, not AGA babies determines Lung function in adulthood, r2 = 0.44, p<0.001
The early roots of ‘COPD’
• Some fundamental preliminary observations
• ‘COPD’ vs. premature airflow obstruction
• Safe in the womb?
• Birth right?
• Think beyond the airway
• Summary and conclusions
29 wk
gestation Saccule wall, epithelium
on both sides with double
capillary network.
Myofibroblast and elastin
fibres at intervals along
wall.
Capillaries have coalesced
to form one sheet alveolar
wall is thinner and longer
with less matrix. Muscle and
elastin still at tip
alveolus
Secondary septa
develops from wall led by
elastin produced by
myofibroblast. Capillary
lines both sides with matrix
between
alveolus
Mechanism of formation of alveolar walls
34 wk
38 wk
29 wk
Redrawn from Burri 1967
Nicotine exposure and
septation
0
1
2
3
4
5
6
7
8
9
10
Day 1 Day 7 Day 14 Day 21
Control
Nicotine
* *
* * *p<0.05
Cell Biology International 2014; 18: 747-767
Early Emphysema?
• Proof of concept
studies:
– Early postnatal
hyperoxia and/or
corticosteroid
therapy
• Could nicotine also
be implicated as a
culprit?
• (Also He3 MRI data)
Int J Environ Res Public
Health 2011; 8: 875-98
Placebo
Placebo
Triamcinolone
Nicotine
The early roots of ‘COPD’
• Some fundamental preliminary observations
• ‘COPD’ vs. premature airflow obstruction
• Safe in the womb?
• Birth right?
• Think beyond the airway
• Summary and conclusions
Summary and Conclusions
• COPD is as outmoded as ‘anaemia’ and ‘arthritis’ as
a diagnostic label
• The roots of premature airflow obstruction stretch
back into childhood, antenatally and beyond
• The big issues: smoking, asthma history, viral
infections
• You cannot understand adult airway disease without
knowing about childhood events!
Thanks for listening; Start your ‘COPD’ research in early life!