What is TB?

 Tuberculosis is an infectious disease caused

by bacteria (Mycobacterium tuberculosis)
 The TB bacteria usually attack the lungs but it
can also attack the kidneys, spine & brain. It
is fatal if untreated
 Tuberculosis – Old Disease
 TB present in human
population since 2400
BCE
 Egyptian mummies
shown signs of
tubercular decay in
spine and skull
 History Cont’d
 460 BCE Greece Hippocrates called disease
Phthisis
 Wide spread always fatal
 17th century to the next 200 years epidemic
in Europe called “Great White Plague”
 TB was in America before Columbus
 History Cont’d
 17th century Franciscus Sylvius de la Boe of Amsterdam first to
identify tubercles as a characteristic consistent with TB infection
 English physician Richard Morton confirmed tubercles always
present in the lungs of TB infection
 Gaspard Laurent Bayle (1774-1816) proved tubercles were not
products of TB, but the cause.
 TB appeared in the medical language in connection with Bayle’s
theory
 1720 English physician Benjamin Marten said “TB could be
caused by wonderfully minute living creatures ….”
 He stated lying in bed, eating, drinking, talking or
breathing could spread disease
 History
 March 1882, in Berlin,
Robert Koch proved to
German doctors that
bacilli caused TB
 He became known as
The Father of
Bacteriology
 Receive the Nobel
Prize in Physiology in
1905
 1000

100

50
MORTALITY
rate per 100,000
10 Tb evidenced in 4,000 BC

0.5
1700 1750 1800 1850 1900 1950 2000
YEAR
Mortality from tuberculosis in developed countries
 1000

100
1804 Laennec associates lesions,
50 describes “phthsis”
MORTALITY
rate per 100,000
10 Tb evidenced in 4,000 BC

0.5
1700 1750 1800 1850 1900 1950 2000
YEAR
Mortality from tuberculosis in developed countries
 1839, Shoenlein recognized “tubercle” as
fundamental lesion, ergo “tuberculosis”.
1000

100
1804 Laennec associates lesions,
50 describes “phthsis”
MORTALITY
rate per 100,000
10 Tb evidenced in 4,000 BC

0.5
1700 1750 1800 1850 1900 1950 2000
YEAR
Mortality from tuberculosis in developed countries
 1839, Shoenlein recognized “tubercle” as
fundamental lesion, ergo “tuberculosis”.
1000

100
1804 Laennec associates lesions,
50 describes “phthsis”
MORTALITY
rate per 100,000
10 Tb evidenced in 4,000 BC

0.5
1700 1750 1800 1850 1900 1950 2000
YEAR
Mortality from tuberculosis in developed countries
 1839, Shoenlein recognized “tubercle” as
fundamental lesion, ergo “tuberculosis”.
1000
1882, Koch discovers
mycobacterium tuberculosis

100
1804 Laennec associates lesions,
50 describes “phthsis”
MORTALITY
rate per 100,000
10 Tb evidenced in 4,000 BC

0.5
1700 1750 1800 1850 1900 1950 2000
YEAR
Mortality from tuberculosis in developed countries
 1839, Shoenlein recognized “tubercle” as
fundamental lesion, ergo “tuberculosis”.
1000 1882, Koch discovers
mycobacterium tuberculosis

100
1917 Flu pandemic
1804 Laennec associates lesions,
50 describes “phthsis”
MORTALITY
rate per 100,000
10 Tb evidenced in 4,000 BC

0.5
1700 1750 1800 1850 1900 1950 2000
YEAR
Mortality from tuberculosis in developed countries
 1839, Shoenlein recognized “tubercle” as
fundamental lesion, ergo “tuberculosis”.
1000
1882, Koch discovers
mycobacterium tuberculosis

100
1917 Flu pandemic
1804 Laennec associates lesions,
50 describes “phthsis”
MORTALITY
rate per 100,000
10 Tb evidenced in 4,000 BC

5
1946, Streptomycin used as antibiotic

0.5
1700 1750 1800 1850 1900 1950 2000
YEAR
Mortality from tuberculosis in developed countries
Global Importance
 Tuberculosis – The facts!
 TB is curable but kills 5000 people every day or
2 million per year
 2 billion people (1/3 of world’s population) are
infected with the microbes that cause TB
 1 in 10 people infected with TB microbes will
become sick with active TB in their lifetime
 TB is contagious & spreads through the air: if not
treated each person with active TB infects 10-15
people every year (approx)
 Global importance
 Most prevalent infections of Human beings
 The World Health Organization (WHO)
estimates that 1/3 of the worlds population is
infected with TB
 7 to 9 million new cases occur each year
 The WHO estimates that b/w the year 2000 and
2020 one billion new people will be infected, 200
million will get sick, and 35 million will die
 Global TB report - 2013

 In 2013 almost 480 000 persons developed MDR - TB

 In average 9,0% of them had XDR-TB
 If all of 6,1 millions cases (new and retreatment cases) would be
tested for drug resistance in 2013, nearly 300 000 cases could
be MDR - TB each second case them being in India, China and
Russian Federation.
 In 2013 were detected and diagnosed 136 000 of 300 000 cases
with MDR - TB, that means one of two (45%), in comparison of
one of six in 2009.
 The achievement in MDR - TB detection were facilitated by the
new methods of rapid diagnosis.
 480,000 MDR-TB, 9% with XDR

Highest % in the former

USSR countries

India, China, Russia, Pakistan and Ukraine

have 60% of all MDR-TB cases
 WHO European Region
53 countries

18 countries with high TB burden

1. Armenia 10. Lituania
2. Azerbaidjan 11. R. Moldova
3. Belarus 12. România
4. Bulgaria 13. Rusia
5. Estonia 14. Tadjikistan
6. Georgia 15. Turcia
25 EU countries
7. Kazahstan 16. Turkmenistan
8. Kârgâzstan 17. Ucraina
9. Letonia 18. Uzbekistan
 Why the global increase of TB?
 Population growth
 Urbanisation
 Increasing poverty
 Rates of HIV infection – this weakens the immune
system. If HIV + 100x more likely to develop TB
 Drug resistant TB (costs for LEDCs?)
 Young adults & women aged 15-44 , most at risk
 Poorly managed TB programmes – especially in
LEDCs (Africa & SE Asia)
 The Problem Gets Worse
 Multi-Drug Resistance TB (MDR-TB)-strain of
TB resistant to front line anti-biotic treatment
 Extensively Drug Resistance TB (XDR-TB)-
strain of TB resistant to first and second line
antibiotic treatment
 Confirmed cases in 45 countries
 Requires lengthier and more costly
treatments
 MDR TB is a manmade
problem…..It is costly, deadly,
debilitating, and the biggest threat to our
current TB control strategies.
 Funding gap
 US$ 8 billion per year required for the
response
 US$ 2 billion gap
 US$ 2 billion required for R&D
 Cost per case US$ 100 - 500
 Cost per MDR case US$ 9,000 - 49,000
TB incidence and mortality, R. Moldova
 TB Incidence and TB Mortality, R. Moldova, 1991 - 2013
100% DOTS

6000 160

5632
TB incidence, abs 5471
5325
5154 140

5000
Tb Mortality, abs 4940
4744
4579 134 4632 4673 4681
133 4484
Tb incidence - Rate/100000 128 129 120

4142 National
121 health insurance
4000 TB Mortality - Rate/100000 3820
116
113 114 114
DOTS
108 110 100

DOTS
97
2921 2908 2891 2946 2935 89 Plus
3000 80
2753
2627
2331 2298 2332
67 67 67 69 69 60
63
2000 60
Shortages in public health
53 53 54 financing, including TB service
40

1000 805 797 830

695 734 690 716 712 726 713 736 727 657
549 588 20
457 429 494 492 454
261 273 279 19 19 20 18
16 17 16 16 17 17 17 18 16
13 14 2011–2015
11 10 11 11 NTP 2001 - 2005 NTP 2006 - 2010 NTP 11
0
6 6 6 0

1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013

26
Epidemiological indices
Republica Moldova, 2015
 Global incidence (new case and relapse) –
3599 cases – 88,4 la 100 000 population
 New case– 2854 cases – 70,1 la 100 000
population (HIV-pozitivi – 219 cases – 7,7%)
 Relapse - 745 cases – 18,3 la 100 000
population
 Prevalence – 4278 cases – 105,2 la 100 000
population
 Mortality – 406 cases – 10,0 la 100 000
population (HIV-pozitivi – 84 cases – 20,7%)
Epidemiological indices
Republica Moldova, 2015
 Tuberculosis children150 new cases
18,8/100 000 population:
 0 – 4 ani – 46 cases
 5 – 14 ani – 65 cases
 15 – 18 ani – 39 cases
 MDR TB, new cases and retreatment,
Republic of Moldova, 2003 – 2013, %

%MDR TB Primary
%MDR TB Secondary
80%
68%
70% 65% 64% 64%
59% 61%
60% 52%
50% 51%
50%
38% 39%
40%
30% 24% 25% 26% 24% 25%
19% 22%
18%
20% 13%
10%
10% 6%

0%
2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
 Causes of TB epidemic in Moldova
1.Socio-economical crisis
2.Massive migration of population
3.Unemployment;
4.Shortages in public health financing, including TB service:
a) deficiency of the cooperation between the TB service and both,
Primary Health Care and Public Health Centers;
b) insufficient support of implementation and inadequate
financing of the programme;
c) lack of antituberculosis drug supply during 1996-2001
5.Tuberculosis in prisons

6. High levels of MDR-TB

 Reasons of TB Resistance in Moldova

1. Poor infection control in TB hospitals

2. Low compliance of treatment (massive migration of population,
patient knowledge, health system)
3. The lack in surveillance of the treatment (~ 60% of DOT)
4. Very low treatment success rate of new and re-treatment TB
(62.2%)
5. Increasing of number of patients with TB/HIV co-infection
6. Deficiencies in drug supply during 1997-2001
 Challenges: 5 priorities for action
5 PRIORITIES TO ELIMINATE TB

1. Reaching the “missed” cases

(3 million not in the system)

2. Address MDR-TB as crisis

3. Accelerate response to TB/HIV

4. Increase financing to close

resource gaps

5. Intensify research and ensure

rapid uptake of innovations

Technical Advisory Group meeting, WHO/WPRO. Manila 9-12 December 2014

67th World Health Assembly, Geneva, May 2014
Global projections to 2035
 The End TB Strategy: Vision, goal, targets
Vision: A world free of TB
Zero TB deaths, Zero TB disease, and Zero TB suffering
Goal: End the Global TB epidemic (<10 cases per 100,000)

Target 1 Target 2 Target 3

95% reduction in 90% reduction in TB No affected

deaths due to TB incidence rate families face
(compared with (compared with catastrophic
2015) 2015) costs due to TB
 3 pillars and 4 Principles

Integrated, Bold
patient- policies and Intensified
centered supportive research
TB care systems and
and innovation
prevention
 The End TB Strategy components
1. INTEGRATED, PATIENT-CENTRED CARE AND PREVENTION
A.Earlydiagnosis, universal DST, screening of contacts and high-risk groups
B.Treatment of all, including DR-TB, patient support
C.Collaborative TB/HIV activities, management of co-morbidities
D.Preventive treatment of persons at high risk, vaccination against tuberculosis

2. BOLD POLICIES AND SUPPORTIVE SYSTEMS

A.Politicalcommitment, adequate resources for tuberculosis care and prevention
B.Engagement of communities, civil society, and public and private care providers
C.Universal health coverage policy, regulatory frameworks for notification, vital registration,
rational use of medicines, infection control
D.Social protection, poverty alleviation and actions on other determinants of TB

3. INTENSIFIED RESEARCH AND INNOVATION

A.Discovery,development, rapid uptake of new tools
B.Research to optimize implementation, impact - promote innovations
Mycobacterium
tuberculosis
 Overview Mycobacteria

•There are >70 species of mycobacteria

•Of these, two are major pathogens:

1.Mycobacterium tuberculosis (Koch, 1882)
2.Mycobacterium leprae (Hansen, 1874)

•The remaining mycobacteria are environmental organisms-collectively

known as MOTTS (Mycobacteria Other Than Tuberculosis)

•MOTT organisms are responsible for opportunistic infections, especially

in people with AIDS
 Classification

Mycobacteria belong to the

•Order: ACTINOMYCETALES
•Family: MYCOBACTERIACEAE
•Genus: MYCOBACTERIUM

All mycobacteria are:

1.ACID FAST- i.e. they do not destain with acid and alcohol once stained
with arylmethane dyes
2.AEROBIC
3.CONTAIN MYCOLIC ACIDS
4.THEIR GENOMES HAVE A 59-66% GC CONTENT
5.Resistant to drying and chemical disinfectants
6.Sensitive to heat (Pasteurization) and UV light
 Mycobacterium tuberculosis
 M. tuberculosis and seven very closely related
mycobacterial species (M. bovis, M. africanum,
M. microti, M. caprae, M. pinnipedii, M. canetti
and M. mungi) together comprise what is known
as the M. tuberculosis complex.
 An obligate aerobe
 Non-spore forming, Non-motile
 Cell wall lipid rich (25-60% dry weight of the
organism), mycolic acid – retains acid fast stain
 Virulence factors - Cord factor, sulfatides
 Growth - doubling time of 15-20 hrs
Lipid-Rich Cell Wall of Mycobacterium
Mycolic acids

CMN
Group:
Unusual cell
wall lipids
(mycolic
acids,etc.)

(Purified Protein
Derivative)
 Mycobacterial cell wall

Proteins

Man-capped
lipoarabino-
mannan
Cell
Wall
Mycolic acid

Glycolipids
PM

Arabinogalactan
Cytosol

Peptidoglycan
 Sources of infection

 the patient with pulmonary

tuberculosis
 cattle are the principal reservoir for
M. bovis
 Transmission of TB
 M. tuberculosis is carried in airborne particles, called
droplet nuclei, of 1– 5 microns in diameter
 Infectious droplet nuclei are generated when
persons who have pulmonary or laryngeal TB
disease cough, sneeze, shout, or sing
 Depending on the environment, these tiny particles
can remain suspended in the air for several hours
 M. tuberculosis is transmitted through the air, not by
surface contact
 Ease of transmission depends on duration and proximity
of contact as well as the number of bacteria excreted
 Transmission of TB
 Transmission occurs when a person inhales
droplet nuclei containing M. tuberculosis, and
the droplet nuclei traverse the mouth or nasal
passages, upper respiratory tract, and
bronchi to reach the alveoli of the lungs
 Infection can result from only 1-5 bacteria
entering a terminal alveolus
 Only those with active pulmonary TB are
infectious
Transmission
The principal risk behavior for acquiring TB
infection is breathing.
(Bloom and Murray, 1992)
 Transmission

 Digestive route - transmitted through

cow’s milk before pasteurization

 Mucocutaneous route

 Placental transmission
 Ways of transmission
 Digestive way of transmission by drinking
unpasteurised milk from an infected cow or eating raw or
undercooked meat from an infected animal
 Cutaneous / mucocutaneous way of transmission -
can be identified in the infection of morphopathologists,
surgeons, persons carring out sick animals. It is a
casuistic way of transmission.
 Transplacentary way – in the case of a sick TB patient
with generalised process with an affected placenta, early
decolated placenta and other diseases with a high
permeability of placenta. Is very rare way of
transmission.
Factors that Determine the Probability of
Transmission of M. tuberculosis
 Susceptibility (immune status) of the exposed
individual
 Infectiousness of the person with TB disease is
directly related to the number of tubercle bacilli
that he or she expels into the air. Persons who
expel many tubercle bacilli are more infectious
than patients who expel few or no bacilli
 Environment – environmental factors that affect
the concentration of M. tuberculosis organisms
Factors that Determine the Probability of
Transmission of M. tuberculosis
 Exposure:
 Proximity, frequency, and duration of exposure
 Persons with a long duration of exposure, frequent and
close contact have a high risk for infection, with a rate of
infection of 22%

 Virulence of Mtb strain - the capacity of the Mtb agent

to penetrate, to adapt and multiply in the host organism
 It can modify under the influence of medium factors and
the immune state of the host organism
 Characteristics of a Patient with TB Disease
that are associated with Infectiousness
Factor Description

Clinical •Presence of cough, especially lasting 3 weeks or

longer
•Respiratory tract disease, especially with involvement
of the larynx (highly infectious)
•Failure to cover the mouth and nose when coughing
•Inappropriate or inadequate treatment (drugs,
duration)
Procedure •Undergoing cough-inducing or aerosol-generating
procedures (e.g., bronchoscopy, sputum induction,
administration of aerosolized medications)
Radiographic •Cavitation on chest radiograph
and laboratory •Positive culture for M. tuberculosis
•Positive AFB sputum smear result
Environmental factors that enhance the probability
that M. tuberculosis will be transmitted
 Concentration of infectious droplet nuclei - the more droplet
nuclei in the air, the more probable that M. tuberculosis will be
transmitted
 Space – exposure in small, enclosed spaces
 Ventilation – inadequate local or general ventilation that results in
insufficient dilution or removal of infectious droplet nuclei
 Air circulation – recirculation of air containing infectious droplet
nuclei
 Specimen handling - improper specimen handling procedures that
generate infectious droplet nuclei
 Air Pressure - positive air pressure in infectious patient’s room that
causes M. tuberculosis organisms to flow to other areas
Questions?