chronic respiratory disease the acceptable epidemic?

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


100

200

500

1000

1500

Mo

rta

lity p

er

100,0

00

pe

r ye

ar

40 60 80 100 120 140 160


0

.01

.02

.03

.04

Den

sity

60 80 100 120 140 16040


black

Caucasian



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


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


black

Caucasian

Using separate adjustments for black and white


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

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


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.


“…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

chronic respiratory disease the acceptable epidemic?

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