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Module 1
Overview: Tuberculosis, the global emergency
Purpose
To provide you with the basic terms and concepts related to
tuberculosis infection and its diagnosis and control.
Prerequisite
modules
None
Module time
1 hour 15 minutes
Learning
objectives
At the end of this module, you will be able to:
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Content outline
comment on the worldwide and local TB epidemic;
define MDR-TB and XDR-TB;
explain the MDR-TB and XDR-TB problem;
describe the forms of TB and how TB is transmitted;
comment on methods for TB laboratory diagnosis;
describe the new Stop TB Strategy;
explain the role of the NTP and the role and functions of the
laboratory network;
explain the importance of AFB microscopy, culture and DST
in TB control
• TB overview
• Definition of MDR-TB and XDR-TB
• Transmission and forms of TB
• TB diagnosis: advantages and limitations of microscopy and
culture
• Risk of infection and disease in immunocompetent and HIVinfected people
• Stop TB Strategy and the importance of culture and DST
• The role of the national TB programme and the laboratory
network
Annex
Stop TB Strategy at a glance
INTRODUCTION
Worldwide, 1.7 million people die of tuberculosis each year.
In this first decade of the 21st century, the world remains challenged by infectious diseases, and by
tuberculosis (TB) in particular. Annually, 1.7 million people still die from the disease, while
increased deaths are due to drug-resistant TB. In addition, co-infections of TB and human
immunodeficiency virus (HIV) are threatening world health still further.
The spread of TB is also favoured by the fact that the length of treatment (at least 6 months) with
four drugs and the improvement in health status early in the course of therapy may induce the
patient to stop the treatment before its completion – which leads to the development of drugresistant forms of TB.
WHAT IS TUBERCULOSIS?
Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis and occasionally by
M. bovis; these are the two main pathogenic species within the M. tuberculosis complex1. These
bacteria are also known as tubercle bacilli because they produce characteristic lesions called
tubercles. When sputum specimens or other clinical specimens containing mycobacteria are
examined microscopically (after staining of smears with carbol-fuchsin), tubercle bacilli and other
mycobacteria appear red. These bacteria are "acid-fast”, meaning that they retain the stain even
after the smear is treated with a decolorizing solution – hence the term acid-fast bacilli (AFB).
TRANSMISSION AND FORMS OF TUBERCULOSIS
Tuberculosis affects the lungs in more than 80% of cases (referred to as pulmonary TB or PTB
cases). It spreads from the primary lung lesions to other parts of the body via the blood stream,
lymphatic and bronchial systems or by direct spreading. In this way TB may affect any organ and is
then known as extrapulmonary TB (EPTB). Diagnosis of EPTB is often difficult and should be
made by a physician.
Transmission of TB bacilli is by air. When a TB patient with open lung lesion coughs, a large
number of aerosols are produced containing TB bacilli in them; these aerosols dry in the air,
leaving behind droplet nuclei which are smaller in size and contain TB bacilli. These droplet nuclei
remain suspended in air for a considerable long time. When someone inhales these droplet nuclei
of size <3µm, due to small size they reach the alveoli and initiate the infection. The alveolar
macrophages engulph the TB bacteria and try to kill them by phago-lysozme mechanism. Most of
the time the TB bacilli are killed but some times they escape the killing and reside inside the
macrophage and cause disease to the lings in few months to few years. The macrophages can
also carry the bacilli in them to different parts of the body and can cause extra pulmonary
tuberculosis.
Tubercle bacilli are killed by the ultraviolet (UV) rays present in direct sunlight but can survive in
darkness or in a humid environment for several hours or even days.
The higher the number of infectious sources spreading bacilli
within a community, the greater the transmission.
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The complex currently includes the following species: M. tuberculosis, M. bovis, M. africanum, M. canetti, M. microti.
An individual is at greater risk of infection when there is continuous or prolonged exposure, in a
confined space, to a person with sputum smear-positive PTB. The risk of transmission from a
patient with smear-negative PTB is lower.
RISK OF DISEASE
Development of disease following infection depends on the individual's susceptibility. Overall, only
about 10% of infected people develop active TB, half of them within the first year after infection; the
other half will become sick years later. These rates are higher in people living with HIV/AIDS.
MDR-TB AND XDR-TB
Multidrug-resistant tuberculosis (MDR-TB) is a form of TB caused by mycobacteria strains resistant
to at least isoniazid and rifampicin. MDR-TB is a global threat, with a case-fatality rate2 of 50%.
Therapy of MDR-TB is long and expensive: it requires 18 months of a comprehensive regimen of
second-line drugs.
Global surveillance indicates that drug-resistant TB is present everywhere. It is especially severe in
parts of China and in countries of the former Soviet Union. WHO has identified some “hot-spot”
regions in Africa and Eastern Europe, where the incidence of MDR strains among new cases
exceeds 3%.
Recently, extensively drug-resistant strains (XDR) have emerged as a new global threat. XDR TB
is defined as TB strains resistant to isoniazid, rifampicin (definition of MDR) and to:
(i) any fluoroquinolone, and
(ii) at least 1 of the 3 injectable second-line drugs (capreomycin, kanamycin, amikacin).
XDR TB has very high mortality rate and there are very few options to cure these patients.
Definitions of drug resistance
Drug resistance among new cases
Resistance among new cases is defined as the presence of resistant isolates of M. tuberculosis in
patients who, in response to direct questioning, deny having had any prior anti-TB treatment (for
as much as 1 month) and, in countries where adequate documentation is available, for whom
there is no evidence of such a history. Drug resistance among new cases is used to evaluate
recent transmission.
Drug resistance among previously treated cases
Resistance among previously treated cases is defined as the presence of resistant isolates of M.
tuberculosis in patients who, in response to direct questioning, admit having been treated for
tuberculosis for 1 month or more or for whom, in countries where adequate documentation is
available, there is evidence of such a history.
In earlier reports, resistance among previously treated patients was used as a proxy for acquired
resistance. However, evidence shows that this patient category is comprised of patients who have
acquired resistance, patients who have been primarily infected with a resistant strain and
subsequently failed therapy, and patients who have been reinfected. Resistance among previously
treated cases is therefore not a useful proxy for true acquired resistance.
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Case-fatality rate: number of deaths due to the disease/total number of patients with that disease.
TB DIAGNOSIS
TB diagnosis can be done by smear microscopy and/or culture. Each technique has its advantages
and limitations.
Smear microscopy
Early laboratory diagnosis of tuberculosis still relies on the examination of stained smears. For
universal application in resource-limited countries, microscopy of sputum smears is the best choice
of diagnostic method. The technique is simple, inexpensive, and efficient in detecting the most
infectious cases of PTB. Since its yield is highly dependent on careful execution, the technicians or
auxiliary personnel who perform smear microscopy are the most important element in the fight
against TB for the majority of the population in these countries.
The limitations of smear microscopy are:
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low sensitivity;
stains both dead and live mycobacteria;
failure to distinguish tubercle bacilli from other mycobacteria.
Culture
Bacteriological culture provides a definitive diagnosis of tuberculosis. Its primary advantage over
sputum microscopy is that it can detect far lower numbers of bacilli (approximately 10 bacilli/ml of
sputum compared with at least 5000 bacilli/ml of sputum for microscopy). Culture thus increases
the potential for diagnosis of TB at early stages of disease, treatment failures, extrapulmonary TB,
and TB in children and in HIV-positive patients who usually have low bacilli loads and are usually
smear-negative. Culture increases the number of TB case found, often by 30-50%. Moreover,
culture allows both species identification and drug susceptibility testing (DST).
The main limitations of culture are:
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slow growth of M. tuberculosis;
technically demanding;
greater need for infrastructure (qualified and trained staff, equipment such as biological safety
cabinet, centrifuges, incubators, and additional safety measures).
In settings where the capacity exists and microscopy is optimized, culture procedures should be
introduced. As indicated in the Stop TB Strategy, culture should always be performed in the
following situations:
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diagnosis of cases with clinical and radiological signs of pulmonary TB where smears are
repeatedly negative;
diagnosis of extrapulmonary TB;
diagnosis of childhood TB;
diagnosis of TB among HIV-positive adults and children;
diagnosis and monitoring of MDR- and XDR-TB.
The Stop TB Strategy also indicates that culture should be used for periodic surveys of the
prevalence of drug resistance. The technique could also be used to investigate high-risk individuals
who are symptomatic, e.g. laboratory workers, health care workers looking after drug-resistant
patients, or relapse, failure and chronic cases.
THE ROLE OF THE NATIONAL TUBERCULOSIS PROGRAMME
The national tuberculosis programme (NTP) is a joint effort of the government and the community
that aims to reduce, and in the long term eliminate, the suffering caused by TB. The objectives of
the NTP are to reduce mortality, morbidity and disease transmission while avoiding the
development of drug resistance, and to do this by using the technical knowledge and health
resources available in the country.
The NTP accomplishes its objectives by:
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early detection of infectious cases, and
appropriate treatment until the illness is cured.
The goals of the NTP are to reach the TB control targets:
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Millennium Development Goals 2006 (MDG 2006), Target 8 – to halt and begin to reverse the
incidence of TB by 2015.
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Targets linked to the MDG and endorsed by the Stop TB Partnership:
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by 2015, reduce TB prevalence and death rates by 50% relative to 1990;
by 2050, eliminate TB as a public health problem (<1 case per million population).
In countries with a high TB burden, the fight against TB can be successfully conducted within the
setting of an NTP using the WHO recommended strategy for TB control.
STOP TB STRATEGY
DOTS is the internationally recommended strategy for TB control in response to the global TB
emergency. The new Stop TB Strategy was launched in 2006 on World TB Day – 24 March and
revised in 2009. (See Annex 1 for a description of all the components of the new Stop TB
strategy.)
The new Stop TB Strategy 2006–2015 calls for the introduction/strengthening of culture services.
Expansion of culture should be progressive and at the appropriate level of the health system. WHO
recommends the establishment of one quality-assured culture facility per approximately 5 million
population in middle- and low-income countries.3 As indicated in the Global Plan to Stop TB, 50%
of the global population should have access to culture and DST by 2010, and more than 5 billion
people will be covered by these services by 2015. Well-trained laboratory staff and an upgrading of
laboratory facilities are therefore essential.
ORGANIZATION OF LABORATORY SERVICES
Levels of laboratory services
Tuberculosis laboratory services should be fully integrated within the TB control programme, which
should in turn form part of each country’s overall primary health care programme.
Tuberculosis laboratory services should therefore be organized according to the three levels of
general health services:
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peripheral laboratory
intermediate laboratory
central laboratory.
The activities performed at each level differ in complexity:
Peripheral laboratories
Peripheral laboratories should be capable of performing smear microscopy using the Ziehl–
Neelsen (ZN) staining technique for sputum specimens following the quality assurance
requirements.
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This figure is for guidance only figure and must be refined by individual countries according to the epidemiological
situation, infrastructure and national policy.
Intermediate laboratories
In addition to performing the functions of peripheral laboratories, intermediate laboratories should
be capable of providing supervision, monitoring, training, quality assurance for peripheral
laboratories. Intermediate laboratories perform culture and identification of M.tuberculosis. They
may also perform DST under the strict supervision of the National Reference Laboratory.
Central laboratory
The central laboratory is the highest level of the service and should be capable of performing
microscopy, mycobacterial culture and drug susceptibility testing, as well as species identification.
The responsibilities of the central laboratory include:
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Organization and provision of quality assurance and proficiency testing for intermediate and
peripheral laboratories.
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Surveillance of TB drug resistance.
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Participation in epidemiological and operational research.
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Development of TB laboratory guidelines, setting of national standards and implementation of
policies.
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Technical standardization: appropriate methods and techniques must be selected to improve
the work quality of the entire network, to provide a cost-effective training of its staff members,
and to obtain a uniform and reliable recording/reporting system for the NTP. The preparation
and periodical updating of the national TB laboratory technical manual and of standard
operating procedures (SOPs) for the laboratory network are important responsibilities of the
national reference laboratory (NRL).
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Training: the NRL must train people according to the “train the trainers” system on
standardized procedures, etc., according to the NTP’s needs and priorities.
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Supervision: regular and continuing supervision of all laboratories of the network (which
includes external quality assessment, EQA, at all levels) is another important task of the NRL.
In larger countries, a sequential scheme may be employed: the NRL supervises the
intermediate level directly and the peripheral level indirectly through the intermediate-level
laboratories.
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Planning: once the requirements of bacteriological examinations for the NTP have been
defined in accordance with the NTP’s priorities and available resources, the NRL must plan the
activities and needs of the entire laboratory network.
To fulfil these tasks, the NRL must maintain its own (limited) routine laboratory examination
programme in order to:
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maintain its own high proficiency and its ability to carry out operational research, such as the
evaluation of new methods or new indicators;
perform microscopy EQA, by rechecking of slides or preparation of panels of slides and training
staff members from the intermediate laboratories. Similarly, if DST is decentralized, perform
DST EQA by preparation of panels of M.tuberculosis strains and training staff from
intermediate laboratories.
KEY MESSAGES
 Tuberculosis is a poverty-related disease affecting millions of people annually.
 Not all infected individuals will develop the active disease.
 MDR-TB, XDR-TB and TB-HIV coinfection are threats to TB control globally.
 Transmission is airborne, and mainly from pulmonary TB smear-positive cases, whose
detection and treatment are essential for control of the disease.
 Microscopy is the main diagnostic technique in resource-limited countries. Although a
simple technique, it requires highly committed staff to reach its full efficiency.
 Culture is a more sensitive technique than microscopy and can help to increase the
detection rate.
 DOTS is a key component of the global strategy to stop TB.
 TB control is organized in national tuberculosis control programmes, which integrate
laboratory services at peripheral, intermediate, and central levels.
Module 1: Review
Find out how much you have learned by answering these questions.
What is TB and how is it transmitted?
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What is the global burden of TB?
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What is MDR-TB? And XDR-TB?
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What are the advantages of culture over microscopy for TB diagnosis?
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What is the role of the national tuberculosis control programme?
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