John Bunyan (1628-1688)

‘the captain of all these men of

death’
In ‘The Life and Death of Mr
Badman’
 The three captains of the 20th
and 21st centuries
• Tuberculosis

• HIV/AIDS

• Malaria

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 Sources
• Health Protection Agency

• Centre for Disease Control +

Prevention

• World Health Organisation

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 References
• www.hpa.org.uk/TB
• www.cdc.gov/health/diseases
• Hayward, A.C. & Coker, R.J. (2000) Could
a tuberculosis epidemic occur in London
as it did in New York? Emerging Infectious
Diseases 6 No. 1 12-16.
• www.who.org

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 Causative agents of tuberculosis

• Mycobacterium • Mycobacterium
tuberculosis complex tuberculosis
• Mycobacterium
africanum
• Mycobacterium bovis
• Bacille Calmette et
Guerin

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Current status worldwide
 Tuberculosis: some rough figures

• WHO estimate 10 million new cases per

annum

• Mortality 3 million per annum

• Prevalence of carriage: 2 billion

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 Latest TB notification rates

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 Tuberculosis: estimated new cases
(1997 + 2003)
Region 1997 2003
Africa 1,276,341 2,372,000
Americas 466,075 370,000
E. Mediterr. 561,192 634,000
S. East Asia 3,078,750 3,062,000
Europe 422,990 439,000
Western 1,530,497 1,933,000
Pacific
Total 7,325,849 8,810,000
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 Key epidemiological factors
• Increasing population sizes
• Continued migration from rural to urban
areas
• Associated poverty and overcrowding
• Deterioration of public health
infrastructures
• HIV pandemic

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 HIV and tuberculosis
• Where HIV is increasing in incidence, so, too, is
tuberculosis
• HIV has greatly increased number of cases of
TB
• HIV = greatest risk factor that ensures infection
with M. tuberculosis progresses to active
disease
• Active tuberculosis may influence course of HIV
infection

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 Tuberculosis: key issues

• Carriage and dormancy

• Infection and reactivation
• Vaccination and screening
• Drug therapy: resistance and non-
compliance
• HIV/AIDS

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The importance of the
laboratory
 Laboratory investigations
• May be key in diagnosis since TB is a
chronic disease with insidious onset
• Sputum is the key clinical specimen
• Microscopy: Ziehl-Neelsen staining for
acid fast bacilli (AFB) was the mainstay
• Phenol auramine staining and fluorescent
microscopy is preferred when it is
affordable
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 Acid fast bacilli

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 Lab investigations: 2
• Culture has always traditionally relied on
an enriched, selective medium:
Lowenstein-Jensen agar in slopes
• M. tuberculosis grows as a rough, buff +
tough colony in 2-3 weeks
• Sputum must be processed to eliminate
faster growing bacteria
• Sensitivity testing: specialised – performed
in reference laboratories
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 Rough, buff and tough

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 Laboratory investigations: 3
• M,C +S as described remains in use in
most countries where TB is a major
disease
• In UK, for example, automation (Bactec
systems) and molecular biology have had
an impact
• These are expensive: reagents, facilities,
machines and maintenance

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 Molecular techniques
• Identification of an isolate
• Detection of bacteria in clinical
material
• Detection of resistance genes
• Investigation of multiple drug
resistance
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 Conventional investigations

• S. pyogenes • M. tuberculosis
• Throat swab • Sputum
• Direct microscopy • Ziehl-Neelsen or
• Isolation on blood agar in auramine fluorescence
24h • Isolation on
• Confirmation of identity Lowenstein-Jensen
• Sensitivity testing slopes after 3 weeks
• Antibody detection § Sensitivity testing is
slow
§ No antibody testing

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The disease
 Transmission
• Typically spread in aerosols and so
usually presents as pulmonary disease
• Milk and M. bovis
• Can have TB of any tissue or organ
following dissemination from lungs
• Some strains, e.g. from ISC, are more
likely to produce disseminated disease
• Miliary TB in children
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 Consequences of exposure
• Clearance

• Carriage

• Disease

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 Disease progression: 1

• Inhalation of bacilli is typically followed by

ingestion by alveolar macrophages; some
bacteria may survive intracellularly
• Establishment of a primary infection involves
production of a walled off tubercle in which
bacteria are contained but can persist
• No symptoms but carriage; if no spread: latency
• If bacilli spread, cell-mediated immune response
is stimulated

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 Disease progression: 2
• Active disease as spread to lymph nodes occurs
+ is accompanied by fever, weight loss, chills,
night sweats, weakness, no appetite
• These are non specific and are as a result of
the immune response – diagnosis = difficult!
• Macrophages release their contents, causing
local tissue destruction; lung necrosis around
the tubercles that becomes visible on X ray
• Caseous cavities are formed; consumption

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 Disease progression: 3
• Tubercle bacilli will grow in these aerobic
cavities, further stimulating the destructive
immune response
• Sputum may be blood-flecked and patient
will experience coughs and chest pains
• In this open TB, sputum is AFB positive
and the individual is contagious!
• May have spread to other body sites via
the lymphatics
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 Disease progression: 4
• Reactivation: an old TB infection (may not
have had previous symptoms) that has
become active
• Why?
• Re-infection: active TB due to acquisition
of a new infection in a patient who has had
a previous infection

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In the UK
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 Epidemiology in England and Wales: 1
• Steady decline since WW2 ceased in
1980s
• Increases seen in late 80s and early 90s
that are continuing
• Key features include association of
disease with males aged 15-34 years and
females aged 35-64 years; also increase
in non-respiratory disease

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 Epidemiology in England + Wales: 2

• Less of a disease of majority, more of a

disease of minorities
• 1998: 56% of cases were in people born
abroad
• Substantial increase in those from Africa
• Higher urban rates, especially in London,
45% of cases (2006)

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 Epidemiology in London
• In London, East London and the City have
the highest incidence of TB
• Over 50% of these cases are in the
homeless
• In Asian and African populations, it is not
just seen in new arrivals
• Incidence of co-infection with HIV is low
but has increased since 1998
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Control measures
 Control of TB in E + W
• Prompt and effective treatment of
cases
• Examination of contact of cases
• Routine screening of those at high
risk
• National BCG vaccination programme
• Coordinating role of the HPA
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 Methods of Surveillance in UK
• Notifications: statutory requirement for
clinicians to report all suspected or diagnosed
cases (trends in incidence)
• Death certificate data: office of national
Statistics publishes data on deaths in UK
annually (mortality rates)
• Laboratory reports: voluntary reporting by
labs.
• Mycobnet: reference centres report to HPA
which collates details of drug resistance
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 Tuberculin skin testing
• Heaf test • Mantoux test
• 6 small needles • Injection of tuberculin
introduce tuberculin protein into skin using
protein into skin syringe and needle
• Raised red reaction 7 • Site is read 48h later
days later indicates for similar signs
positive result: prior
exposure

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 BCG: Bacille Calmette-Guerin
• Live, attenuated developed in France from
a strain of M. bovis
• Given if skin test negative although babies
may not be tested
• Vaccine is estimated to offer 70-80%
protection in UK for children + neonates
• Immunity has been shown to last at least
15 years but it does NOT give 100%
protection
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 Drug therapy

• Biology of mycobacteria: slow growing and

dividing
• Long term therapy and side effects
• Non-compliance
• (multiple) drug resistance

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 Key (1st line) antibiotics
• Isoniazid
• Rifampicin
• Pyrazinamide
• Ethambutol
• Streptomycin

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 (Multiple) drug resistance in E + W

• Only a small % of isolates display MDR

• There has been a small increase since
1998
• Currently in North London: an outbreak of
isoniazid resistant TB – first case was from
Nigeria

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 Extremely drug resistant TB
• A major problem for the future!
• XDR TB
• Resistant to at least rifampicin + isoniazid
of 1st line drugs
• Resistant to at least 3 of the 6 2nd line
drugs
• Potentially untreatable disease; e.g. in
Kwazulu-Natal region of S. Africa
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 M. bovis + badgers

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 Background
• In 1930s + 1940s, significant % of deaths
in UK were due to M. bovis
• Often scrofula: cervical lymph node TB,
from milk
• Milk pasteurisation and cattle slaughter
following tuberculin testing means risk now
is negligible
• TB disease in cattle is now increasing
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 Should badgers be killed?
• M. bovis can be transmitted between
animals
• M. bovis is endemic in badgers
• 2 issues: how can badgers be culled
effectively + humanely?
Does this culling help control
spread of M. bovis?

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Other mycobacteria
 Leprosy: M. leprae
• Once of worldwide distribution, now confined to
Tropics, approx. 70% of cases in India, (N.B.
also Indonesia and Myanmar)
• Can cause great disfigurement, bacteria target
Schwann cells, causing nerve damage and
hence anaesthesia and paralysis
• Injury to infected areas (skin, peripheral nerves)
and immune response result in visible lesions

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 Leprosy: 2
• Effects may be v obvious in later stages
but it is curable and not highly infectious –
needs prolonged close contact for
transmission
• Bacteria are v slow growing and
incubation period may be 5 years and it
may be 210 years before symptoms
appear

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 Leprosy: 3
• In some countries, diagnosis may be
missed
• Disease presentation is varied and
depends on immune response:
tuberculoid: few lesions/few bacteria good
immunity/ easy to treat lepromatous: many
lesions/bacteria poor immunity/difficult to
treat

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 (TT) (BT) (BB) (BL) (LL)

Vigorous host response No effective immune response

Tuberculoid Leprosy Borderline Leprosy Lepromatous Leprosy

Less than five clearly defined Patients can progress to either Usually multiple poorly defined
skin lesions containing few bacilli. tuberculoid or lpromatous forms skin lesions teeming with bacilli.
Often referred to as paucibacilliary of the disease. Often referred to as multibacilliary
(smear negative) disease. (smear positive) disease.
Non-infectious. Infectious form requiring prolonged
Short course treatment - 6 months treatment - 2 years in the UK

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 Leprosy: 4
• 1991:WHO planned to eliminate leprosy
by 2000
• Still >500,000 cases reported each year
• Drugs are successful: dapsone, rifampicin,
clofazimine (6-24 months)
• Isolated and shunned communities are a
problem since diagnosis has improved

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 Global Leprosy Situation 2000

India

>5

>10

Prevalence rate per

100,000 population

Source: WHO Weekly Epidemiological Record 14 July 2000

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 UK: Number of patients on Central Leprosy Register 2001
by country of birth
60

50
No. leprosy patients

40

30

20

10

0
ISC Africa LAC Asia UK Other
Country of birth
Source: Central Leprosy Register database PHLS / CDSC

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 NTM Nontuberculosis
mycobacteria
• Includes all species not in M. tuberculosis
complex and M. leprae
• Over 80 species; ubiquitous in the
environment, often in water
• Were originally classified into Runyon
groups by speed of growth and pigment
production
• Now can be identified with HPLC for
species-specific cell wall mycolic acids
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 NTM: 2
• Most are not pathogenic
• Some may be important in i/c patients
• M. avium complex – now best known for
causing disseminated disease in later
stages of AIDS
• Other species can cause skin lesions, e.g.
M. ulcerans + Buruli ulcer and M. marinum
+ fish fancier’s disease/ fish tank
granuloma
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