Chronic Respiratory Disease – the acceptable epidemic?
Peter Burney
National Heart and Lung Institute
Imperial College, London
Milroy Lecture Royal College of Physicians
26th October 2015
Dr Gavin Milroy
• 1805 Born in Edinburgh • 1824 MRCS (Edin) • Set up in general practice in London • 1847: LRCP • 1849-50: Superintendent Medical Inspector General Board of Health • 1852: Sanitary Report on Jamaica • 1853: FRCP • 1855-6: Sanitary Commission to the Army in the East (Crimea) • 1858: Secretary to the Social Science Association’s inquiry into the use of
quarantine • 1862: College committee enquiring into leprosy for the colonial office • 1886: Died leaving a legacy of £2,000 to establish a lectureship on “state
medicine and public health, and subjects connected therewith”
Dr Milroy’s suggestions
Acknowledgements
• I should preface my remarks by acknowledging generous funding over the years from:
– The Department of Health
– The Medical Research Council
– The Wellcome Trust
– The European Community
Good reasons to ignore the problem as a research topic
• The problem is not important
• The questions have all been answered
Global death ranks for the top 25 causes 1990 and 2010 from: Lozano et al. Lancet 2012; 380: 2095-2128
Global years lived with disability (YLDs) ranks for the top 25 causes 1990 and 2010
from: Vos et al. Lancet 2012; 380: 2163-2196
The British Hypothesis
Smoking
Irritation
Mucus Hypersecretion
Inflammation
Airflow Obstruction
Death from COPD
Charles Fletcher, Richard Peto and the high water mark of the “anti-British” hypothesis
All cause death ratio by FEV1/Ht3
1
1.5
2
2.5
3
3.5
4
4.5
>2SD below mean 1-2 SD below
mean
0-1 SD bleow
mean
> Mean
FEV1/Ht3
Death
Rati
o
1
1.5
2
2.5
3
3.5
4
4.5
Phlegm all day Phlegm part of day No Phlegm
Death
Rati
o
Phlegm Production
All cause death ratio by Phlegm production unadjusted and Adjusted for FEV1/Ht3
Unadjusted Adjusted for FEV1/Ht3
• A meta-analysis of several studies with information on ventilatory function, phlegm production and subsequent survival showed that all deaths and deaths from COPD were strongly associated with lung function, but only marginally with phlegm production.
The British Hypothesis after 1976
Smoking
Irritation
Mucus Hypersecretion
Inflammation
Airflow Obstruction
Death from COPD
Longitudinal studies of FEV1 and survival in general population samples
Study Reported effect Outcome studied Ref.
Tecumseh YES Survival Higgins, 1970
Baltimore YES Survival Beaty, 1984
Gothenborg YES Survival Olofson, 1987
New Guinea YES Survival Anderson 1988
Whitehall YES Survival Ebi-Kryston, 1988
Washington Co. YES Survival Tockman, 1989
Six Cities YES Survival Speizer, 1989
Copenhagen YES Survival Lange, 1990
Whitehall YES Survival Strachan, 1992
Renfrew YES Survival Hole, 1996
Busselton YES Survival Knuiman, 1999
Buffalo YES Survival Schunemann, 2000
Whitehall (GPO) YES Survival Ferrie, 2007
John Hutchinson, 1811–1861, inventor of the spirometer and “vital capacity”
0
5
10
15
20
25
30
<Mean-164mL Mean +/- 164 mL >Mean +164 mL
Vital Capacity adjusted for height
Ra
te/1
000
pe
rso
n y
ears
Deaths/1000 person years Invalided out/1000 person years
Survival of recruits in the Guards regiments according to Vital Capacity
from T Graham Balfour. Contribution to the Study of Spirometry, 1860
Vital Capacity and Cardiovascular Mortality in the Framingham Study: 20 year follow up
from Kannell, Hubert and Lew. American Heart Journal 1983.
Cardiovascular Mortality/1000 by vital capacity
index Whole population and population selected as non-smokers
free of pulmonary disease and heart failure
0
5
10
15
20
25
12- 32- 36- 40- 44- 48- 52- 56- 60- 64-
Vital Capacity Index (ml/inch)
Mo
rtali
ty f
rom
CV
D
/1000/ year
Men Women Male (selected) Female (selected)
Partial regression coefficients for
cardiovascular mortality
Men Women
Vital Capacity
Index -0.29** -0.53**
Age 0.43** 0.49**
Systolic BP 0.32** 0.75**
Glucose
Intolerance 0.13** 0.27**
Cholesterol 0.43 0.16*
Relative Weight -0.21** -0.10
Heart Rate 0.18** 0.08
Smoking 0.16* 1.81*
** P<0.01; * P<0.05
Association of different measurements of ventilatory function with survival
Adjustment Confounders*
MEN Hazard
ratio
95% CI p
FEV1 0.91 0.87, 0.96 <0.001
FVC 0.87 0.82, 0.93 <0.001
FEV1/ FVC 0.99 0.91, 1.08 0.88
WOMEN
FEV1 0.88 0.83, 0.93 <0.001
FVC 0.83 0.77, 0.89 <0.001
FEV1/ FVC 1.00 0.87, 1.14 1.00
* Age, Height, BMI, Waist-Hip ratio, Sitting height, Income, Working status, Most recent occupation, Ever smoked, Current smoker, Pack years smoked, Education, Systolic blood pressure.
Association of different measurements of ventilatory function with survival
Adjustment: Confounders Confounders + FEV1 or FVC
MEN Hazard ratio
95% CI p Hazard ratio
95% CI p
FEV1 0.91 0.87, 0.96 <0.001 0.99 0.91, 1.07 0.77
FVC 0.87 0.82, 0.93 <0.001 0.88 0.80, 0.98 0.019
FEV1/ FVC 0.99 0.91, 1.08 0.88
WOMEN
FEV1 0.88 0.83, 0.93 <0.001 1.01 0.90, 1.15 0.83
FVC 0.83 0.77, 0.89 <0.001 0.81 0.70, 0.95 0.008
FEV1/ FVC 1.00 0.87, 1.14 1.00
COAD Mortality (women < 60 years)
Prevalence of Cigarette Smoking (adult women)
http://www.who.int/ceh/publications/en/map09b.jpg
Biomass smoke exposure and risk of COPD: a meta-analysis
NOTE: Weights are from random effects analysis
Overall (I-squared = 81.2%, p = 0.000)
Dennis 1996
Orozco-Levi 2006
Caballero 2008
Menzes 1994
Liu 2007
study
Albalak 1999
Regalado 2006
Chapman 2005
Sezar 2006
Ekici 2005
Perez-Padilla 1996
Akhtar 2007
Dossing 1994
Jindal 2006
Kiraz 2003
2.24 (1.72, 2.90)
3.92 (1.70, 9.10)
4.50 (1.40, 14.20)
1.50 (1.22, 1.86)
1.86 (1.16, 2.99)
3.11 (1.63, 5.94)
Odds ratio (95% CI)
2.50 (1.25, 5.00)
1.50 (0.50, 4.30)
1.33 (1.09, 1.61)
6.61 (2.17, 20.18)
1.40 (1.20, 1.70)
3.90 (2.00, 7.60)
2.51 (1.65, 3.83)
63.80 (7.90, 2709.00)
1.03 (0.84, 1.28)
23.20 (6.30, 85.40)
100.00
%
5.24
3.50
10.71
8.34
6.73
Weight
6.33
3.87
10.82
3.69
10.96
6.55
8.85
0.74
10.71
2.96
2.24 (1.72, 2.90)
3.92 (1.70, 9.10)
4.50 (1.40, 14.20)
1.50 (1.22, 1.86)
1.86 (1.16, 2.99)
3.11 (1.63, 5.94)
Odds ratio (95% CI)
2.50 (1.25, 5.00)
1.50 (0.50, 4.30)
1.33 (1.09, 1.61)
6.61 (2.17, 20.18)
1.40 (1.20, 1.70)
3.90 (2.00, 7.60)
2.51 (1.65, 3.83)
63.80 (7.90, 2709.00)
1.03 (0.84, 1.28)
23.20 (6.30, 85.40)
100.00
%
5.24
3.50
10.71
8.34
6.73
Weight
6.33
3.87
10.82
3.69
10.96
6.55
8.85
0.74
10.71
2.96
1.5 1 2.24 10 100
Data from Eisner et al. AJRCCM 2010; 182: 693-718
Exposure to biomass fires for heating (per 10 years, assuming a linear effect)
NOTE: Weights are from random effects analysis
Overall (I-squared = 0.0%, p = 0.626)
South Africa
Country
USA
Canada
Poland
Austria
UK
Turkey
Iceland
China
1.01 (0.94, 1.10)
1.08 (0.85, 1.38)
ES (95% CI)
0.97 (0.73, 1.28)
0.91 (0.61, 1.36)
0.97 (0.82, 1.15)
1.10 (0.89, 1.37)
0.80 (0.61, 1.05)
1.05 (0.91, 1.21)
1.25 (0.73, 2.13)
1.35 (0.72, 2.53)
100.00
%
10.45
Weight
7.87
3.79
22.00
12.97
8.40
30.81
2.15
1.56
1.01 (0.94, 1.10)
1.08 (0.85, 1.38)
ES (95% CI)
0.97 (0.73, 1.28)
0.91 (0.61, 1.36)
0.97 (0.82, 1.15)
1.10 (0.89, 1.37)
0.80 (0.61, 1.05)
1.05 (0.91, 1.21)
1.25 (0.73, 2.13)
1.35 (0.72, 2.53)
100.00
%
10.45
Weight
7.87
3.79
22.00
12.97
8.40
30.81
2.15
1.56
1.1 .2 .5 1 2 5 10
Philippines excluded because none of the 7 participants exposed to biomass fires for heating had COPD
Data from Hooper et al. Eur Respir J. 2012; 39: 1343–1353
Adjusted Odds Ratio of airflow obstruction from current cooking fuel use
Women Men
OR 95%CI OR 95%CI
Gas/Electricity 1 0.95, 1.06 1 0.80, 1.25
Coal 1.10 1.04, 1.17 1.01 0.80, 1.25
Wood 0.91 0.88, 0.95 1.04 0.88, 1.22
Other 0.68 0.48, 0.96 2.03 1.72, 4.72
Smith et al. Eur Respir J. 2014; DOI: 10.1183/09031936.00152413
Prevalence of Chronic Airway Obstruction by pack-years smoked and
sex
0
5
10
15
20
25
30
0 5 10 15 20 25 30 35
Mean Pack Years Smoked
% F
EV
1/F
VC
< L
LN
Male (FEV1/FVC<LLN) Female (FEV1/FVC<LLN)
COAD Mortality (women < 60 years)
Social class gradient by cause of death
0
50
100
150
200
250
300
350
All causes Ca bronchus TB COPD
Cause of death
Sta
nd
ard
ised
Mo
rtali
ty R
ati
o
Professional
Managerial
Skilled non-manual
Skilled manual
Partly skilled
Unskilled
COAD mortality under age 60 by GNI per capita by country
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0 50000 100000 150000 200000
GNI per capita by country ($US)
Mo
rtali
ty f
rom
CO
AD
(%
)
COAD Male < 60
COAD Female < 60
Proportion of FVC < LLN by sex and Gross National
Income/capita
0.00
10.00
20.00
30.00
40.00
50.00
60.00
70.00
80.00
0 10,000 20,000 30,000 40,000 50,000 60,000 70,000 80,000 90,000
Gross National Income/capita ($US)
% F
VC
<LLN
Male
Female
Distribution of FEV1 according to Age, Sex and Ethnicity
Differences in lung volumes (mL) per % point in
African ancestry in three US Studies
Kumar et al. NEJM 2010; 363: 321-330
Study FEV1 FVC FEV1/FVC
Cardia (Men) -8.14** -12.12**** 0.04
Cardia (Women) -5.54**** -5.41*** -0.03
CHS -2.39* -3.46** 0.02
HABC -3.99**** -5.50**** 0.01
* p=0.009; ** p=0.004; *** p=0.007; ****p<0.001 Adjusted for age, (sex,) pack years, BMI, height, height2, and study site.
A simple conclusion
GENES
LUNG FUNCTION
RACE
A complicating thought
GENES
LUNG FUNCTION
RACE
LIVING CONDITIONS
% employed in professional or managerial occupations according to race and skin colour in the USA
redrawn from Hughes and Hertel. Social Forces 1990; 68 (4): 1112-1120
0
5
10
15
20
25
30
WHITE BLACK
Pe
rce
nta
ge
Race/Skin Colour
% employed in professional or managerial occupations according to race and skin colour in the USA
redrawn from Hughes and Hertel. Social Forces 1990; 68 (4): 1112-1120
0
5
10
15
20
25
30
WHITE Light or Very
Light
Medium BLACK Dark or Very
Dark
Race/Skin Colour
Pe
rce
nta
ge
An equally plausible hypothesis
GENES
LUNG FUNCTION
RACE
LIVING CONDITIONS
Prevalence of different genetic variants in Caucasian and Asian populations
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
TNF 308G/A GSTM1Null GSTP1|105V EPHXY113H EPHXH139R
Pre
vale
nce
(9
5%
CI)
Genetic Variant
Asian Prevalence
CaucasianPrevalence
Redrawn from: Smolonska et al. Am J Respir Crit Care Med Vol 180. pp 618–631, 2009
Odds ratios for “COPD” associated with specific genotypes by ethnicity
Redrawn from: Smolonska et al. Am J Respir Crit Care Med Vol 180. pp 618–631, 2009
0
0.5
1
1.5
2
2.5
3
3.5
TNF 308G/A GSTM1Null GSTP1|105V EPHXY113H EPHXH139R
Od
ds
Rat
io (
95
%C
I) f
or
"CO
PD
"
Genotype
Asian OR
Caucasian OR
FVC (% predicted) and Mortality in Women ARIC Study
0
.01
.02
.03
.04
Den
sity
60 80 100 120 140 16040
% predicted FVC (Caucasian equations)
black
Caucasian
Using Caucasian standards for both groups
Differences in FVC (L) and effects of adjustment for confounding
Male Female
Adjusted for White -
Black 95% CI
White -
Black 95% CI
Unadjusted 0.73 0.80 to 0.66 0.44 0.49 to 0.40
Differences in FVC (L) and effects of adjustment for confounding
Male Female
Adjusted for White -
Black 95% CI
White -
Black 95% CI
Unadjusted 0.73 0.80 to 0.66 0.44 0.49 to 0.40
+ age, height 0.75 0.80 to 0.70 0.53 0.56 to 0.49
+ sitting height, waist-hip
ratio, BMI 0.73 0.80 to 0.67 0.43 0.46 to 0.39
+ ever smoked, current
smoker, pack years 0.72 0.77 to 0.65 0.41 0.45 to 0.37
+ income, working status,
most recent occupation,
education 0.69 0.76 to 0.63 0.41 0.45 to 0.37
FVC (% predicted) and Mortality in Women ARIC Study
100
200
500
1000
1500
Mo
rta
lity p
er
100,0
00
pe
r ye
ar
40 60 80 100 120 140 160
% predicted FVC (Caucasian equations)
0
.01
.02
.03
.04
Den
sity
60 80 100 120 140 16040
% predicted FVC (Caucasian equations)
black
Caucasian
Using Caucasian standards for both groups
FVC (% predicted) and Mortality in Women ARIC Study
100
200
500
1000
1500
Mo
rta
lity p
er
100,0
00
pe
r ye
ar
40 60 80 100 120 140 160
% predicted FVC (ethnic group-specific equations)
100
200
500
1000
1500
Mo
rta
lity p
er
100,0
00
pe
r ye
ar
40 60 80 100 120 140 160
% predicted FVC (Caucasian equations)
0
.01
.02
.03
.04
Den
sity
40 60 80 100 120 140 160
% predicted FVC (ethnic group-specific equations)
0
.01
.02
.03
.04
Den
sity
60 80 100 120 140 16040
% predicted FVC (Caucasian equations)
black
Caucasian
Using separate adjustments for black and white
Using Caucasian standards for both groups
Odds ratio of grade 2 dyspnoea with FVC and FEV1/FVC
Grønseth et al. Eur Respir J. 2014 June ; 43(6): 1610–1620
COAD mortality under age 60 by GNI per capita by country
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0 50000 100000 150000 200000
GNI per capita by country ($US)
Mo
rtali
ty f
rom
CO
AD
(%
)
COAD Male < 60
COAD Female < 60
Global COPD deaths 1990 and 2010
-
1
2
3
4
5
6
1990 Observed 2010 Expected 2010 Observed
CO
PD
de
ath
s (m
illio
ns)
COPD Deaths
Global population by age and sex 1990 and 2010
-
50.00
100.00
150.00
200.00
250.00
40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80+
Po
pu
lati
on
(M
illio
ns)
Age Group
Female 1990
Male 1990
Female 2010
Male 2010
Global COPD deaths 1990 and 2010
-
1
2
3
4
5
6
1990 Observed 2010 Expected 2010 Observed
CO
PD
de
ath
s (m
illio
ns)
COPD Deaths
2010 Expected
Global COPD deaths 1990 and 2010
-
1
2
3
4
5
6
1990 Observed 2010 Expected 2010 Observed
CO
PD
de
ath
s (m
illio
ns)
COPD Deaths
2010 Expected
Age-sex specific COPD mortality rates in 1990 and 2010
0
20
40
60
80
100
120
140
160
40-44years
45-49years
50-54years
55-59years
60-64years
65-69years
70-74years
75-79years
80+years
Age
-Sex
Sp
eci
fic
CO
PD
Mo
rtal
ity/
10
0,0
00
Age group
Female2010
Male1990
Male2010
Female1990
Change in COPD deaths due to different factors
-100
-80
-60
-40
-20
0
20
40
60
PopulationGrowth
PopulationAging
Age-sex specificrates
ACTUAL
% C
han
ge in
CO
PD
de
ath
s re
sult
ing
Population Growth
Population Aging
Age-sex specific rates
ACTUAL
Changes in smoking index 1990-2010 by region
0
50
100
150
200
250
300
350
400
Smo
kin
g In
dex
1990
2010
Changes in gross national income per capita 1990-2010 by region
0
5000
10000
15000
20000
25000
30000
35000
40000
45000
50000
Gro
ss N
atio
nal
Inco
me
/cap
ita
($U
S, p
pp
)
1990
2010
Fraction of the change in COPD mortality rates between 1990 and 2010 attributable to changes
in gross national income and smoking
Variable Population
Attributable Fraction
95% CI
GNI 26.23 4.71 to 47.74
Smoking Index 3.91 3.22 to 4.59
From: Burney et al. Eur Respir J 2015; 45(5):1239-47
Actual research spend in the UK (2004) by clinical area (£M)
0
50
100
150
200
250
Act
ual
res
earc
h s
pe
nd
20
04
(£
M)
Data from: UK Health Research Analysis 2009/10 UK Clinical Research Collaboration 2012
Research spend 2004 and 2010 by clinical area (£M)
0
50
100
150
200
250
300
350
Act
ual
Sp
end
(£
M)
"Actual spend (£M)" 2004 "Actual spend (£M) 2010
Data from: UK Health Research Analysis 2009/10 UK Clinical Research Collaboration 2012
Increasing gap in funding for respiratory disease
2004/5 (£ M) 2009/10 (£M)
Total spend on specific clinical areas 750 1,216
Target respiratory spend* 62 101
Actual respiratory spend 10 28
Gap in spend 52 73
* Target assumes an equal spend/Disability Adjusted Life Year lost in the UK.
Data from: UK Health Research Analysis 2009/10 UK Clinical Research Collaboration 2012
“…those inflicted are inclined to accept the complaint as inevitable, as something troublesome but not serious. Those called upon to treat it do not find it sufficiently interesting to study closely, yet records in England and Wales show that when mortality and morbidity are taken together, bronchitis is the most important of all diseases and at the same time a most preventable disease”.
“…those inflicted are inclined to accept the complaint as inevitable, as something troublesome but not serious. Those called upon to treat it do not find it sufficiently interesting to study closely, yet records in England and Wales show that when mortality and morbidity are taken together, bronchitis is the most important of all diseases and at the same time a most preventable disease”.
E.L. Collis, Professor of Preventive Medicine in Cardiff J Ind Hyg Toxicol 1923; 5: 264-276.
What causes chronic lung disease? How can it be prevented?
How should it be identified and diagnosed? How should it be managed?
0.00
0.00
0.01
0.10
1.00
10.00
100.00
1901 1906 1911 1916 1921 1926 1931 1936 1941 1946 1951 1956 1961 1966 1971 1976 1981 1986 1991
RA
TE
/1,0
00
YEAR OF DEATH
MALE DEATHS from COPD &c.
15-24 YEARS
25-34 YEARS
35-44 YEARS
45-54 YEARS
55-64 YEARS
65-74 YEARS
Adjusted Odds Ratio of airflow obstruction from current heating fuel use
Women Men
OR 95%CI OR 95%CI
Gas/Electricity 1 0.91,1.10 1 0.78, 1.28
Coal 0.93 0.88, 0.99 1.07 0.90, 1.27
Wood 1.06 0.99, 1.13 1.04 0.87, 1.26
Other 2.65 2.15, 3.27 2.03 0.83, 4.98
Smith et al. Eur Respir J. 2014; DOI: 10.1183/09031936.00152413
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