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UCLH Members Event: Tuberculosis 22nd June 2015
Dave Moore, London School of Hygiene & Tropical Medicine & UCLH
Phil Gothard, Hospital for Tropical Diseases, UCLH
Al Story, TB Find & Treat Service, UCLH
Thoracoplasty
TB Notifications in England & Wales
Where did TB come from
and why is it going away?
“Phthisis was the most considerable of the diseases which then prevailed and the only one which proved fatal to many persons.” Hippocrates Book I, Of the Epidemics
Pleural adhesions from chronic infection 6-8 year old girl, Thebes, 1500-500 BC
Vac tomb, Hungary, 1808 Mummified body 36 year old man Died after haemorrhage from mouth Microscopic appearance of chest material Strongly PCR+ for M tuberculosis
Human origins and civilisation
2.6 – 2.8 million y Early Hominids
Archaeological record
200,000 y Modern Man
Anatomy, Y-c’some, mitochondria
50 - 60,000 y Dispersal East
Rapid (1km/y) ‘coastal express’
Mitochondrial DNA, tool archaeology
20 - 40,000 y Dispersal North
Slow ‘founder effect’
West from Asia not via the Nile
Human origins and civilisation
2.6 – 2.8 million y Early Hominids
Archaeological record
200,000 y Modern Man
Anatomy, Y-c’some, mitochondria
50 - 60,000 y Dispersal East
Rapid (1km/y) ‘coastal express’
Mitochondrial DNA, tool archaeology
20 - 40,000 y Dispersal North
Slow ‘founder effect’
West from Asia not via the Nile
Human origins and civilisation
2.6 – 2.8 million y Early Hominids
Archaeological record
200,000 y Modern Man
Anatomy, Y-c’some, mitochondria
50 - 60,000 y Dispersal East
Rapid (1km/y) ‘coastal express’
Mitochondrial DNA, tool archaeology
20 - 40,000 y Dispersal North
Slow ‘founder effect’
West from Asia not via the Nile
Where did M tuberculosis come from?
Co-evolution of pre-MTB from soil with early hominids
(2 - 3 million years)
Mycobacterium prototuberculosis
= Most recent common ancestor
Evolutionary bottleneck 20-40,000 y ago
Sequence data show it was located in E Africa
Hunter gatherers
=> bottleneck for highly virulent pathogens
Neolithic society (10,000 years ago)
=> Settled agriculture Denser population
Ecological disruption (cultivation)
Economic and political inequality
Nutritional narrowing
Human origins and civilisation
Hunter gatherers
=> bottleneck for highly virulent pathogens
Neolithic society (10,000 years ago)
=> Settled agriculture Denser population
Ecological disruption (cultivation)
Economic and political inequality
Nutritional narrowing
Human origins and civilisation
TB caused 1 in 4 of all deaths in C18th and early C19th
TB caused 1 in 4 of all deaths in C18th and early C19th
Death rates for tuberculosis per million per annum, left hand scale (dots) and all causes per million, right hand scale (squares), for England and Wales.
Changing incidence: 1850 to 1910
Changing incidence: 1850 to 1910
TB rates have fallen steadily since 1850
Improvements in social conditions: poverty and overcrowding?
Comparison of social factors
with tuberculosis and other diseases of poverty
(cholera, dysentery, infant mortality)
Registrar Generals Annual Reports
• Mortality statistics: 3 notifiable diseases
• Census data: housing & size of resident population
• Statistics: average real earnings
Changing incidence: 1850 to 1910
TB rates have fallen steadily since 1850
Improvements in social conditions: poverty and overcrowding
Comparison of social factors
with tuberculosis and other diseases of poverty
(cholera, dysentery, infant mortality)
Registrar Generals Annual Reports
• Mortality statistics: 3 notifiable diseases
• Census data: housing & size of resident population
• Statistics: average real earnings
Changing incidence: 1850 to 1910
TB rates have fallen steadily since 1850
Improvements in social conditions: poverty and overcrowding
Comparison of social factors
with tuberculosis and other diseases of poverty
(cholera, dysentery, infant mortality)
Registrar General’s Annual Reports
• Mortality stats: 3 notifiable diseases
• Census data: housing & size of resident population
• Statistics: average real earnings
Death rates for infants per 1000 live births, left hand scale (dots), and cholera (squares) per million, right hand scale (E&W)
Changing incidence: 1850 to 1910
Changing incidence: 1850 to 1910
Fall in TB mortality far exceeds improvement in social conditions Why? TB affects young adults, and kills children Reduced fertility of TB-susceptible families Relative increase in TB-resistant population
Hypothesis BCG & Rx remove this selective pressure Modern population may be more susceptible No decline in ‘white population’ incidence (late C20)…
Changing incidence: 1850 to 1910
1825 Elizabeth age 10 1825 Maria age 11 1849 Anne age 29 1848Emily age 30 1855 Charlotte age 38
Five siblings All died from TB None had children
Fall in TB mortality far exceeds improvement in social conditions
Why?
TB affects young adults, and kills children
Reduced fertility of TB-susceptible families
Relative increase in TB-resistant population
Hypothesis
BCG & Rx remove this selective pressure
Modern population may be more susceptible
Changing incidence: 1850 to 1910
Alternative hypotheses for decline in mortality
Thomas McKeown & RG Record (1962) “progressive improvement in the standard of living” Sir Stanley Woodwark (1938) “together with rickets, scuvy and gout disease …the influence of diet can clearly be traced” Sir Arthur Newsholme (1923) “reduced exposure to infection brought about by the segregation of consumptives in Poor Law Infirmaries”
Alternative hypotheses for decline in mortality
Thomas McKeown & RG Record (1962) “progressive improvement in the standard of living” Sir Stanley Woodwark (1938) “together with rickets, scuvy and gouty disease …the influence of diet can clearly be traced” Sir Arthur Newsholme (1923) “reduced exposure to infection brought about by the segregation of consumptives in Poor Law Infirmaries”
Alternative hypotheses for decline in mortality
Thomas McKeown & RG Record (1962) “progressive improvement in the standard of living” Sir Stanley Woodwark (1938) “together with rickets, scuvy and gout disease …the influence of diet can clearly be traced” Sir Arthur Newsholme (1923) “reduced exposure to infection brought about by the segregation of consumptives in Poor Law Infirmaries”
VH Springett (1952)
1) Reduction in number of persons infected
ISOLATION (AND VACCINATION)
2) Reduction in number of infected persons developing disease
HOST DENFENCE
3) Reduction in those with TB who die from the disease
TREATMENT
Alternative hypotheses for decline in mortality
VH Springett (1952)
1) Reduction in number of persons infected
ISOLATION (AND VACCINATION)
2) Reduction in number of infected persons developing disease
HOST DEFENCE
3) Reduction in those with TB who die from the disease
TREATMENT
Alternative hypotheses for decline in mortality
New Poor Law (1834)
Bentham’s Utilitarianism: ‘correct level of poor rate’
Malthus’s doctrine of population growth opposes Old Poor Law
Alternative hypotheses for decline in mortality
New Poor Law (1834)
TB disease of young and productive => destitute
No longer allowed to receive alms at home
Workhouses admit sick paupers and become public hospitals
Workhouse expansion 1860s onwards
London 1869: 28,600 inmates
11,000 sick (39%)
(cf 4000 general hospital beds)
Alternative hypotheses for decline in mortality
New Poor Law (1834)
TB disease of young and productive => destitute
No longer allowed to receive alms at home
Workhouses admit sick paupers and become public hospitals
Workhouse expansion 1860s onwards
London 1869: 28,600 inmates
11,000 sick (39%)
(cf 4000 general hospital beds)
Alternative hypotheses for decline in mortality
Old St Pancras workhouse
1834 Phase 1 Initial New Poor Law Segregation
1870 Phase 2 Expansion of workhouses
Koch’s discovery
(WW1)
1920 Phase 3 7x expansion in TB beds
Sputum microscopy
Artificial pnuemothorax => smear negative
1950 Phase 4 Chemotherapy
Alternative hypotheses for decline in mortality
TB in contemporary London
Rich world
5% of all cases
Rare cause of death
Treated by doctors / MDT
CT imaging common
Bronchoscopy if smear negative
Extensive microbiology
Hospital isolation facilities
Enthusiastic contact tracing
Empirical 4-drug therapy (eth)
Completion rates >95%
Low drug resistance
Targeted DOT in practice
HIV co-infection unusual
Poor world
98% of all cases
Common cause of death
Treated by nurses
CXR is too expensive
Limited sputum microscopy
No drug susceptibility testing
Overcrowded wards
Limited contact tracing
Empirical 4-drug therapy (strep)
Completion rates <75%
High drug resistance (expensive)
Universal DOTS in theory
HIV co-infection common
Rich world
5% of all cases
Rare cause of death
Treated by doctors / MDT
CT imaging common
Bronchoscopy if smear negative
Extensive microbiology
Hospital isolation facilities
Enthusiastic contact tracing
Empirical 4-drug therapy (eth)
Completion rates >95%
Low drug resistance
Targeted DOT in practice
HIV co-infection unusual
Poor world
95% of all cases
Common cause of death
Treated by nurses
CXR is too expensive
Limited sputum microscopy
No drug susceptibility testing
Overcrowded wards
Limited contact tracing
Empirical 4-drug therapy (strep)
Completion rates <75%
High drug resistance (expensive)
Universal DOTS in theory
HIV co-infection common
Rich world
5% of all cases
Rare cause of death
Treated by doctors / MDT
CT imaging common
Bronchoscopy if smear negative
Extensive microbiology
Hospital isolation facilities
Enthusiastic contact tracing
Empirical 4-drug therapy (eth)
Completion rates >95%
Low drug resistance
Targeted DOT in practice
HIV co-infection unusual
Poor world
95% of all cases
Common cause of death
Treated by nurses
CXR is too expensive
Limited sputum microscopy
No drug susceptibility testing
Overcrowded wards
Limited contact tracing
Empirical 4-drug therapy (strep)
Completion rates <75%
High drug resistance (expensive)
Universal DOTS in theory
HIV co-infection common
Rich world
5% of all cases
Rare cause of death
Treated by doctors / MDT
CT imaging common
Bronchoscopy if smear negative
Extensive microbiology
Hospital isolation facilities
Enthusiastic contact tracing
Empirical 4-drug therapy (eth)
Completion rates >95%
Low drug resistance
Targeted DOT in practice
HIV co-infection unusual
Poor world
95% of all cases
Common cause of death
Treated by nurses
CXR is too expensive
Limited sputum microscopy
No drug susceptibility testing
Overcrowded wards
Limited contact tracing
Empirical 4-drug therapy (strep)
Completion rates <75%
High drug resistance (expensive)
Universal DOTS in theory
HIV co-infection common
Rich world
5% of all cases
Rare cause of death
Treated by doctors / MDT
CT imaging common
Bronchoscopy if smear negative
Extensive microbiology
Hospital isolation facilities
Enthusiastic contact tracing
Completion rates >95%
Low drug resistance
Targeted DOT in practice
HIV co-infection unusual
Poor world
95% of all cases
Common cause of death
Treated by nurses
CXR is too expensive
Limited sputum microscopy
No drug susceptibility testing
Overcrowded wards
Limited contact tracing
Empirical 4-drug therapy (strep)
Completion rates <75%
High drug resistance (expensive)
Universal DOTS in theory
HIV co-infection common
Rich world
5% of all cases
Rare cause of death
Treated by doctors / MDT
CT imaging common
Bronchoscopy if smear negative
Extensive microbiology
Hospital isolation facilities
Enthusiastic contact tracing
Completion rates >95%
Low drug resistance
Targeted DOT in practice
HIV co-infection unusual
Poor world
95% of all cases
Common cause of death
Treated by nurses
CXR is too expensive
Limited sputum microscopy
No drug susceptibility testing
Overcrowded wards
Limited contact tracing
Completion rates <75%
High drug resistance (expensive)
Universal DOTS in theory
HIV co-infection common
Rich world
5% of all cases
Rare cause of death
Treated by doctors / MDT
CT imaging common
Bronchoscopy if smear negative
Extensive microbiology
Hospital isolation facilities
Enthusiastic contact tracing
Completion rates >95%
Low drug resistance
Targeted DOT in practice
HIV co-infection unusual
Poor world
95% of all cases
Common cause of death
Treated by nurses
CXR is too expensive
Limited sputum microscopy
No drug susceptibility testing
Overcrowded wards
Limited contact tracing
Completion rates <75%
High drug resistance (expensive)
Universal DOTS in theory
HIV co-infection common
Rich world
2% of all cases
Rare cause of death
Treated by doctors / MDT
CT imaging common
Bronchoscopy if smear negative
Extensive microbiology
Hospital isolation facilities
Enthusiastic contact tracing
Completion rates >95%
Low drug resistance
Targeted DOT in practice
HIV co-infection unusual
Poor world
98% of all cases
Common cause of death
Treated by nurses
CXR is too expensive
Limited sputum microscopy
No drug susceptibility testing
Overcrowded wards
Limited contact tracing
Completion rates <75%
High drug resistance (expensive)
Universal DOTS in theory
HIV co-infection common
TB in contemporary London
7290 cases
2nd highest rate in Western Europe
250% increase in MDR since 2000
95% increase in migrant cases
5% decrease in native cases
60
0
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
0
1,000
2,000
3,000
4,000
5,000
6,000
7,000
8,000
9,000
10,000
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Rate
(p
er
100,
000)
Nu
mb
er
of
cases
Year
Number of cases Rate per 100,000
Tuberculosis case reports and rates, UK, 2004-2013
Tuberculosis in the UK: 2014 report
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI), Office for National Statistics (ONS) Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
61
Tuberculosis case reports and rates by PHE Centre,
England, 2013 35.5
17.3
11.2
15.6
9.5
14.3
6.1 6.2
9.1 9.2 9.2
5.1 4.6 4.8
3.5
0
5
10
15
20
25
30
35
40
0
500
1,000
1,500
2,000
2,500
3,000
3,500
Rat
e (
pe
r 1
00
,00
0)
Nu
mb
er
of
Cas
es
PHE Centre
Number of cases Rate per 100,000
Tuberculosis in the UK: 2014 report
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI), Office for National Statistics (ONS) Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
62
• Three-year average tuberculosis case rates by local area*, UK, 2011-2013
*England – Local authorities, Wales and Scotland – Health Boards, NI – Country level
© Crown copyright and database rights 2014 Ordnance Survey 100016969
London
Tuberculosis in the UK: 2014 report
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI), Office for National Statistics (ONS) Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
0
10
20
30
40
50
60
70
80
90
100
0
100
200
300
400
500
600
700
800
900
1,000
1,100
1,200
Rate
(p
er
100,0
00)
Nu
mb
er
of
cases
Age group (years)
UK Born Non-UK Born Rate in UK Born Rate in Non-UK Born
63
Tuberculosis case reports & rates by age group & place of birth,
UK, 2013
Tuberculosis in the UK: 2014 report
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI),Labour Force Survey (LFS) Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
64 Tuberculosis in the UK: 2014 report
Proportion of TB cases by deprivation quintile residence, England, 2013
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI), Index of Multiple Deprivation (IMD 2010) Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
2,962
1,871
1,006
644 427
0
10
20
30
40
50
60
70
80
90
100
Most deprived 2nd quintile 3rd quintile 4th quintile Least deprived
Pro
po
rtio
n o
f T
B c
ases (
%)
Deprivation Quintiles
North Central London TB Service (2014-5): patients by country of birth
160 cases
76% born overseas
49 countries
Somalia 14
India 12
Eritrea 11
Bangladesh 6
Pakistan 5
Philippines 5
Turkey 5
NCL TB Service: region of birth 2014-5: 160 patients
Africa
Asia
Americas
Middle East
Europe
UK
41 (26%) in hospital
16 (10%) spinal
65 (41%) pulmonary
24 (15%) smear positive
10 (6%) cavities
9 (6%) HIV+
4 (3%) Isoniazid resistant
1 (0.6%) MDR
North Central London TB Service (2014-5): clinical complexity
15 (9%) not registered with a GP
30 (19%) with adherence risk factors
Homeless 18
Drug use 10
Mental Health 9
Prison 8
Alcohol 4
26 (16%) on DOT
42 (26%) enhanced case management
North Central London TB Service (2014-5): social complexity
70
Most frequent countries of birth for non-UK born TB cases, UK, 2013
* Where country of birth was known; **Years
Country of birth Number of cases Percentage of cases*
Median time since entry to UK (IQR)**
India 1,615 29.8 5 (2 -13)
Pakistan 1,103 20.4 7 (2 -22)
Somalia 292 5.4 9 (4 -13)
Bangladesh 248 4.6 7 (3 -18)
Nepal 170 3.1 3 (2 -6)
Nigeria 164 3.0 7 (3 -11)
Philippines 136 2.5 8 (5 -12)
Zimbabwe 105 1.9 11 (7 -12)
Sri Lanka 95 1.8 7 (3 -13)
Kenya 84 1.6 22 (8 -37)
Romania 70 1.3 2 (0 -4)
Afghanistan 67 1.2 6 (2 -11)
Poland 66 1.2 5 (2 -7.5)
Eritrea 62 1.1 4 (2 -7)
China 56 1.0 7 (4 -11)
Others (each <1%)
1,082 20.0 5 (1 -13)
Total* 5,415 100 7 (3 -14)
Tuberculosis in the UK: 2014 report
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI) Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
71
Time between entry to the UK & TB diagnosis for
non-UK born TB cases by year, UK, 2013
Tuberculosis in the UK: 2014 report
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI), Office for National Statistics (ONS) Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
72
Proportion of TB case reports by site of disease, UK, 2004-2013
* With or without extra-pulmonary disease
Tuberculosis in the UK: 2014 report
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI) Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
0
10
20
30
40
50
60
70
80
90
100
2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Pro
po
rtio
n o
f cases (
%)
Year
Pulmonary* Extra-pulmonary only
73
Tuberculosis case reports by site of disease, UK, 2013 Site of disease* Number of cases Percentage**
Pulmonary 4,096 52.1
Extra-thoracic lymph nodes 1,874 23.9
Unknown extra-pulmonary 931 11.9
Intra-thoracic lymph nodes 916 11.7
Pleural 673 8.6
Other extra-pulmonary 689 8.8
Gastrointestinal 432 5.5
Bone – spine 353 4.5
Bone – other 220 0.5
Miliary± 211 2.8
CNS – meningitis 172 2.7
Genitourinary 145 2.2
CNS – other 129 1.8
Cryptic 39 1.6
Laryngeal 19 0.2
Tuberculosis in the UK: 2014 report
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI) Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
*With or without disease at another site **Percentage of cases with known site of disease (8751) ±For Scotland cases, this includes both cryptic and miliary site CNS-Central Nervous System Total percentage exceeds 100% due to infections at more than one site
74 Tuberculosis in the UK: 2014 report
Treatment completion at 12 months for drug sensitive TB cases with expected treatment duration <12 months*, UK, 2003-2012
* Excludes initial and amplified to rifampicin resistant TB and MDR-TB cases and MDR-TB treated cases and those with CNS, spinal, miliary or cryptic disseminated TB
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI) Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
0
10
20
30
40
50
60
70
80
90
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012
Pro
po
rtio
n o
f cases (
%)
Year
75 Tuberculosis in the UK: 2014 report
TB outcome at 12 months for drug sensitive TB cases with expected treatment duration <12 months*, UK, 2012
Treatment outcome n %
Completed 6,438 82.8
Died 345 4.4
Lost to follow-up 307 3.9
Still on treatment 446 5.7
Stopped 79 1.0
Not evaluated** 159 2.0
Total 7,774
* Excludes initial and amplified to rifampicin resistant TB and MDR-TB cases and MDR-TB treated cases and those with CNS, spinal, miliary or cryptic
disseminated TB
** Not evaluated includes missing, unknown and transferred out
Source: Enhance Tuberculosis Surveillance (ETS), Enhanced Surveillance of Mycobacterial Infections (ESMI) Data as at: May 2014. Prepared by: TB Section, Centre for Infectious Disease Surveillance and Control, Public Health England
76 Tuberculosis in the UK: 2014 report
TB outcome at 24 months for drug resistant cohort, UK, 2011*
*Excludes initial and amplified to rifampicin resistant TB and MDR-TB cases and MDR-TB treatment cases ** Not evaluated includes missing, unknown and transferred out
Treatment outcome n %
Completed 47 48.0
Died 4 4.1
Lost to follow-up 19 19.4
Still on treatment 22 22.4
Stopped 4 4.1
Not evaluated** 2 2.0
Total 98